CC214-2 is a potent and dual inhibitor of mTORC1/mTORC2. Mycobacterium tuberculosis modulates mammalian target of rapamycin (mTOR) signaling to impede autophagy. CC214-2 has the potential to shorten the duration of TB[1].
分子量
383.44
Formula
C20H25N5O3
CAS 号
1228012-18-7
运输条件
Room temperature in continental US; may vary elsewhere.
储存方式
Please store the product under the recommended conditions in the Certificate of Analysis.
参考文献
[1]. Tasneen R, et al. Dual mTORC1/mTORC2 Inhibition as a Host-Directed Therapeutic Target in Pathologically Distinct Mouse Models of Tuberculosis. Antimicrob Agents Chemother. 2021;65(7):e0025321.
CC214-2 is a potent and dual inhibitor of mTORC1/mTORC2. Mycobacterium tuberculosis modulates mammalian target of rapamycin (mTOR) signaling to impede autophagy. CC214-2 has the potential to shorten the duration of TB[1].
分子量
383.44
Formula
C20H25N5O3
CAS 号
1228012-18-7
运输条件
Room temperature in continental US; may vary elsewhere.
储存方式
Please store the product under the recommended conditions in the Certificate of Analysis.
参考文献
[1]. Tasneen R, et al. Dual mTORC1/mTORC2 Inhibition as a Host-Directed Therapeutic Target in Pathologically Distinct Mouse Models of Tuberculosis. Antimicrob Agents Chemother. 2021;65(7):e0025321.
Lenalidomide-d5 is deuterium labeled Lenalidomide. Lenalidomide (CC-5013), a derivative of Thalidomide, acts as molecular glue. Lenalidomide is an orally active immunomodulator. Lenalidomide (CC-5013) is a ligand of ubiquitin E3 ligase cereblon (CRBN), and it causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. Lenalidomide (CC-5013) specifically inhibits growth of mature B-cell lymphomas, including multiple myeloma, and induces IL-2 release from T cells[1][2].
体外研究 (In Vitro)
Stable heavy isotopes of hydrogen, carbon, and other elements have been incorporated into drug molecules, largely as tracers for quantitation during the drug development process. Deuteration has gained attention because of its potential to affect the pharmacokinetic and metabolic profiles of drugs[1].
Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.
分子量
264.29
Formula
C13H8D5N3O3
CAS 号
1227162-34-6
运输条件
Room temperature in continental US; may vary elsewhere.
储存方式
Please store the product under the recommended conditions in the Certificate of Analysis.
参考文献
[1]. Russak EM, et al. Impact of Deuterium Substitution on the Pharmacokinetics of Pharmaceuticals. Ann Pharmacother. 2019;53(2):211-216.
[2]. Krönke J, et al. Lenalidomide induces degradation of IKZF1 and IKZF3. Oncoimmunology. 2014 Jul 3;3(7):e941742.
[3]. Kotla V, et al. Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol. 2009 Aug 12;2:36.
[4]. Lopez-Girona A, et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia. 2012 Nov;26(11):2326-35.
[5]. Rozewski DM, et al. Pharmacokinetics and tissue disposition of lenalidomide in mice. AAPS J. 2012 Dec;14(4):872-82.
[6]. Minzel W, et al. Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models. Cell. 2018 Sep 20;175(1):171-185.e25.
[7]. Nagashima, Takeyuki, et al. PHARMACEUTICAL COMPOSITION COMPRISING BICYCLIC NITROGEN-CONTAINING AROMATIC HETEROCYCLIC AMIDE COMPOUND AS ACTIVE INGREDIENT. Patent. 20170360780A1.
[8]. Omran A, et al. Effects of MRP8, LPS, and lenalidomide on the expressions of TNF-α , brain-enriched, and inflammation-related microRNAs in the primary astrocyte culture. ScientificWorldJournal. 2013 Sep 21;2013:208309.
Lenalidomide (CC-5013), a derivative of Thalidomide, acts as molecular glue. Lenalidomide is an orally active immunomodulator. Lenalidomide (CC-5013) is a ligand of ubiquitin E3 ligase cereblon (CRBN), and it causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. Lenalidomide (CC-5013) specifically inhibits growth of mature B-cell lymphomas, including multiple myeloma, and induces IL-2 release from T cells[1][2].
IC50 & Target[5]
Cereblon
体外研究 (In Vitro)
Lenalidomide is potent in stimulating T cell proliferation and IFN-γ and IL-2 production. Lenalidomide has been shown to inhibit production of pro inflammatory cytokines TNF-α, IL-1, IL-6, IL-12 and elevate the production of anti-inflammatory cytokine IL-10 from human PBMCs. Lenalidomide downregulates the production of IL-6 directly and also by inhibiting multiple myeloma (MM) cells and bone marrow stromal cells (BMSC) interaction, which augments the apoptosis of myeloma cells[2]. Dose-dependent interaction with the CRBN-DDB1 complex is observed with Thalidomide, Lenalidomide and Pomalidomide, with IC50 values of ~30 μM, ~3 μM and ~3 μM, respectively, These reduced CRBN expression cells (U266-CRBN60 and U266-CRBN75) are less responsive than the parental cells to antiproliferative effects Lenalidomide across a dose-response range of 0.01 to 10 μM[3]. Lenalidomide, a thalidomide analog, functions as a molecular glue between the human E3 ubiquitin ligase cereblon and CKIα is shown to induce the ubiquitination and degradation of this kinase, thus presumably killing leukemic cells by p53 activation[5].
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
体内研究 (In Vivo)
The toxicity of Lenalidomide doses up to 15, 22.5, and 45 mg/kg via IV, IP, and PO routes of administration. Limited by solubility in our PBS dosing vehicle, these maximum achievable Lenalidomide doses are well tolerated with the exception of one mouse death (of four total dosed) at the 15 mg/kg IV dose. Notably, no other toxicities are observed in the study at IV doses of 15 mg/kg (n=3) or 10 mg/kg (n=45) or at any other dose level through IV, IP, and PO routes[4].
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
Clinical Trial
分子量
259.26
Formula
C13H13N3O3
CAS 号
191732-72-6
中文名称
来那度胺；雷那度胺
运输条件
Room temperature in continental US; may vary elsewhere.
[1]. Krönke J, et al. Lenalidomide induces degradation of IKZF1 and IKZF3. Oncoimmunology. 2014 Jul 3;3(7):e941742.
[2]. Kotla V, et al. Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol. 2009 Aug 12;2:36.
[3]. Lopez-Girona A, et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia. 2012 Nov;26(11):2326-35.
[4]. Rozewski DM, et al. Pharmacokinetics and tissue disposition of lenalidomide in mice. AAPS J. 2012 Dec;14(4):872-82.
[5]. Minzel W, et al. Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models. Cell. 2018 Sep 20;175(1):171-185.e25.
[6]. Nagashima, Takeyuki, et al. PHARMACEUTICAL COMPOSITION COMPRISING BICYCLIC NITROGEN-CONTAINING AROMATIC HETEROCYCLIC AMIDE COMPOUND AS ACTIVE INGREDIENT. Patent. 20170360780A1.
[7]. Omran A, et al. Effects of MRP8, LPS, and lenalidomide on the expressions of TNF-α , brain-enriched, and inflammation-related microRNAs in the primary astrocyte culture. ScientificWorldJournal. 2013 Sep 21;2013:208309.
Cell Assay [3]
Cell lines NCI-H929 and U266, and DF15 cells are grown in RPMI-I640 medium containing 10% (V/V) heat-inactivated fetal bovine serum supplemented with 2 mM glutamine. To produce Lenalidomide resistant cell lines, NCI-H929 cells are treated continuously (fresh Lenalidomide is added every 3-4 days) with control (final 0.1% DMSO) or low-dose Lenalidomide (1 μM) for 2 months until the proliferation of cells is no longer inhibited by Lenalidomide (1 μM), as determined by cell viability (Vi-cell XR cell viability analyzer), cell proliferation by flow cytometry and cell cycle analysis (propidium iodide staining). After acquisition of resistance to 1 μM, the resistant H929 cell lines are treated with Lenalidomide (10 μM) for a further 4 months. After this period of time, the cell cultures achieved fully establish resistance up to high-dose Lenalidomide (30 μM). Prior to the experiments described here, H929 Lenalidomide-resistant cells are taken out of culture with compounds for 5-7 days before use[3].
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
Animal Administration [4]
Mice[4] Imprinting control region (ICR) mice 8-10 weeks of age are used. Lenalidomide is incompletely soluble at 3.5 mg/mL and above in PBS containing 1% HCl, as visible particulates remained after thorough mixing. Therefore 3 mg/mL is selected as the maximum dosing solution concentration (with no visible particulates). Single, individual mice are initially dosed with 3, 10, or 15 mg/kg IV; 4.5, 15, or 22.5 mg/kg IP; and 9, 30, or 45 mg/kg PO. Additional mice (n=4) are then evaluated at the maximum dose achievable by volume and solubility of Lenalidomide in the dosing solution. All mice are monitored closely for 1 h and re-evaluated for toxicities 3, 6, and 24 h postdose[4].
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
参考文献
[1]. Krönke J, et al. Lenalidomide induces degradation of IKZF1 and IKZF3. Oncoimmunology. 2014 Jul 3;3(7):e941742.
[2]. Kotla V, et al. Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol. 2009 Aug 12;2:36.
[3]. Lopez-Girona A, et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia. 2012 Nov;26(11):2326-35.
[4]. Rozewski DM, et al. Pharmacokinetics and tissue disposition of lenalidomide in mice. AAPS J. 2012 Dec;14(4):872-82.
[5]. Minzel W, et al. Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models. Cell. 2018 Sep 20;175(1):171-185.e25.
[6]. Nagashima, Takeyuki, et al. PHARMACEUTICAL COMPOSITION COMPRISING BICYCLIC NITROGEN-CONTAINING AROMATIC HETEROCYCLIC AMIDE COMPOUND AS ACTIVE INGREDIENT. Patent. 20170360780A1.
[7]. Omran A, et al. Effects of MRP8, LPS, and lenalidomide on the expressions of TNF-α , brain-enriched, and inflammation-related microRNAs in the primary astrocyte culture. ScientificWorldJournal. 2013 Sep 21;2013:208309.
CC-115 is a potent and dual DNA-PK and mTOR kinase inhibitor with IC50s of 13 nM and 21 nM, respectively. CC-115 blocks both mTORC1 and mTORC2 signaling.
IC50 & Target[1]
DNA-PK
13 nM (IC50)
mTOR
21 nM (IC50)
mTORC1
mTORC2
PI3Kα
852 nM (IC50)
体外研究 (In Vitro)
CC-115 inhibits PC-3 cells proliferation with an IC50 of 138 nM. In a kinase selectivity assessment against a panel of 250 protein kinases at 3 μM, only one kinase other than mTOR kinase is identified with more than 50% inhibition (cFMS 57%, IC50=2.0 μM). Of the PI3K related kinases (PIKKs) tested, CC-115 proves to be equipotent against DNA PK (IC50=15 nM) and demonstrates 40 to >1000 fold selectivity against the remaining PIKKs tested; PI3K-alpha (IC50=0.85 μM), ATR (50% inhibition at 30 μM) and ATM (IC50>30 μM). The IC50 values for CC-115 are >10 μM against a panel of CYP enzymes and >33 μM for the hERG (human ether-a-go-go-related gene) ion channel. When screened in a single point assay at 10 μM against a Cerep receptor and enzyme panel only one target is inhibited >50% (PDE3, IC50=0.63 μM)[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
体内研究 (In Vivo)
CC-115 shows good in vivo PK profiles across multiple species with 53%, 76% and ~100% oral bioavailability in mouse, rat and dog, respectively. CC-115 is tested at lower doses of 0.25, 0.5 and 1 mg/kg bid or 1 mg/kg qd, with observed corresponding tumor volume reductions of 46%, 57%, 66% and 57% respectively. CC-115 sustains inhibition though 24 hours. At the 1 mg/kg dose CC-115 shows significant inhibition at 1 and 3 hours, CC-115 demonstrating inhibition through 10 hours. CC-115 is evaluated using both once (qd) and twice (bid) daily dosing schedules[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
Clinical Trial
分子量
336.35
Formula
C16H16N8O
CAS 号
1228013-15-7
运输条件
Room temperature in continental US; may vary elsewhere.
将 2 g 磺丁基醚 β-环糊精加入 5 mL 生理盐水中，再用生理盐水定容至 10 mL，完全溶解，澄清透明
*以上所有助溶剂都可在 上海金畔生物科技有限公司 网站选购。
参考文献
[1]. Mortensen DS, et al. Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors and the Discovery of CC-115. J Med Chem. 2015 Jul 23;58(14):5599-5608.
Kinase Assay [1]
An HTR-FRET substrate phosphorylation assay is employed for mTOR kinase. PI3Kα IC50 determinations are outsourced using the mobility shift assay format. Compounds (e.g., CC-115) are assessed against concentrations of ATP at approximately the Km for the assay, with average ATP Km of 15 μM and 50 μM for the mTOR and PI3K assays, respectively[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
Cell Assay [1]
PC-3 cells are cultured in growth media. For biomarker studies cells are treated for 1 h and then assayed for pS6 and pAkt levels using MesoScale technology. For proliferation experiments, cells are treated with compound (e.g., CC-115) and then allowed to grow for 72 h. All data are normalized and represented as a percentage of the DMSO-treated cells. Results are then expressed as IC50 values[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
Animal Administration [1]
Mice[1] Encouraged by the observed exposures, CC-115 is advanced into single dose PK/PD studies assessing mTOR pathway biomarker inhibition in tumor bearing mice. PC-3 tumor-bearing mice are administered with a single dose of CC-115, dosed orally at either 1 or 10 mg/kg, and plasma and tumor samples are collected at various time points for analysis. Significant inhibition of both mTORC1 (pS6) and mTORC2 (pAktS473) is observed for all compounds and the level of biomarker inhibition correlated to plasma compound levels.
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
参考文献
[1]. Mortensen DS, et al. Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors and the Discovery of CC-115. J Med Chem. 2015 Jul 23;58(14):5599-5608.
CC-885 is a cereblon (CRBN) modulator with potent anti-tumour activity.
IC50 & Target
CRBN[1].
体外研究 (In Vitro)
Acute myeloblatlic leukemia (AML) cell lines, human liver epithelial cell line (THLE-2) and human peripheral blood mononuclear cells (PBMC) are treated with varying concentrations of CC-885, with IC50s of 10×-6-1 μM. The effect of CC-885 on cell proliferation in AML cell lines, THLE-2 and human PBMC is more powerful than Lenalidomide and Pomalidomide with IC50s>10 μM. To address whether the cereblon-dependent degradation of GSPT1 is responsible for the cytotoxic effects of CC-885, a GSPT1 mutant that retains its normal function, but loses CC-885-dependent cereblon binding, is used to distinguish the role of GSPT1 from that of other substrates. CC-885 is tested in 293T HEK cells stably expressing the CC-885-sensitive or -resistant GSPT1 variants. Overexpression of a resistant variant GSPT1Δ(1–138)/(G575N) completely abrogate the CC-885-induced anti-proliferation, whereas overexpression of a CC-885-sensitive variant GSPT1Δ(1-138) only confer partial protection. Similar results are obtained in AML cell lines[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
分子量
440.88
Formula
C22H21ClN4O4
CAS 号
1010100-07-8
运输条件
Room temperature in continental US; may vary elsewhere.
[1]. Mary E. Matyskiela, et al. A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase. Nature. 2016 Jul 14;535(7611):252-7.
Cell Assay [1]
Human cancer cell lines cultured in the growth medium are seeded into black 384-well plates containing DMSO or test compounds such as CC-885 (10×-6-1 μM). The seeding density for each cell line is optimized to allow the cell growth in the linear range during a 3-day culture period. To test the compound effect on cell proliferation in acute myeloid leukaemia (AML) cell lines, 5,000 to 10,000 cells per well in 200 μl complete culture media are seeded into black 96-well plates containing DMSO or test compounds such as CC-885. After 48 or 72 h, cell proliferation is assessed using the CellTiter-Glo (CTG) Luminescent Cell Viability Assay[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
参考文献
[1]. Mary E. Matyskiela, et al. A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase. Nature. 2016 Jul 14;535(7611):252-7.
Iberdomide (CC-220) is an orally active and potent cereblon (CRBN) E3 ligase modulator (CELMoD) with an IC50 of ~150 nM for cereblon-binding affinity. Iberdomide, a derivative of Thalidomide (HY-14658), has antitumor and immunostimulatory activities[1][2].
体外研究 (In Vitro)
Iberdomide (CC-220; 0.01, 0.1, 1, 10 μM; 72-96 hrs) has antiproliferative effects in a panel of multiple myeloma (MM) cell lines (EJM, H929, KMS11, KMS128M, KMS12PE, MM1.S, MM1.R, RPM-8226, U266 cells) across a range of concentrations[1]. Iberdomide (0.1 μM; 96 hrs) induces apoptosis in all MM cell lines[1]. Iberdomide (0.1 μM; 24, 48, 72 hrs) results in time-dependent increases in G0/G1 and sub-G1 cell cycle fractions on H929 cells[1]. Iberdomide leads to rapid Aiolos depletion in the KMS12BM line[1]. Iberdomide (0.1 μM) displays some anti-proliferative activity in two of the Pomalidomide-resistant (PR) lines with cereblon mutations (EJM/PR and H929/PR) along with decreased levels of cereblon protein[1]. Iberdomide (0.1-1000 nM; 72 hrs) equally induces PBMC-mediated killing of both parental MM1.S cells and MM1.S/PR cells[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
体内研究 (In Vivo)
Iberdomide (CC-220; 10 mg/kg; oral gavage) after 6 or 24 hours causes higher hCRBN expression in hC343 splenocytes correlated to deeper IKZF1/3 downregulation in WT (C57BL/6), hC123, or-343, (representing two different transgenic founder lines expressing hCRBN) and mCrbn-/- mice[2].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
Clinical Trial
分子量
449.50
Formula
C25H27N3O5
CAS 号
1323403-33-3
运输条件
Room temperature in continental US; may vary elsewhere.
[1]. Chad C Bjorklund, et al. Iberdomide (CC-220) is a potent cereblon E3 ligase modulator with antitumor and immunostimulatory activities in lenalidomide- and pomalidomide-resistant multiple myeloma cells with dysregulated CRBN. Leukemia. 2020 Apr;34(4):1197-1201.
[2]. Erin W Meermeier, et al. Tumor burden limits bispecific antibody efficacy through T cell exhaustion averted by concurrent cytotoxic therapy. Blood Cancer Discov. 2021 Jul;2(4):354-369.
Kinase Assay [1]
Iberdomide is dissolved in DMSO. In the assay, 60 nM 6Xhis-tagged CRBN-DDB1 is combined with 30 nM cy5-conjugated cereblon modulator and 3 nM LanthaScreen Eu-anti-His Tag antibody in 20 mM HEPES pH 7, 150 mM NaCl, 0.005% Tween-20 assay buffer. FRET is observed by exciting at 340 nm and monitoring emission at 615 nm and 665 nm, and FRET efficiency is determined by the ratio of FRET to non-FRET emission. Competing cereblon modulating compound (Iberdomide) or DMSO carrier is titrated and incubated for 10 min before scanning[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
参考文献
[1]. Chad C Bjorklund, et al. Iberdomide (CC-220) is a potent cereblon E3 ligase modulator with antitumor and immunostimulatory activities in lenalidomide- and pomalidomide-resistant multiple myeloma cells with dysregulated CRBN. Leukemia. 2020 Apr;34(4):1197-1201.
[2]. Erin W Meermeier, et al. Tumor burden limits bispecific antibody efficacy through T cell exhaustion averted by concurrent cytotoxic therapy. Blood Cancer Discov. 2021 Jul;2(4):354-369.
Mezigdomide (CC-92480), a cereblon E3 ubiquitin ligase modulating drug (CELMoD), acts as a molecular glue. Mezigdomide shows high affinity to cereblon, resulting in potent antimyeloma activity[1].
体外研究 (In Vitro)
Mezigdomide is the second cereblon modulator. Mezigdomide-induced loss of Aiolos and Ikaros in cultures of PBMCs resulted in the activation of T cells and increased production of IL-2 and IFN-γ. Mezigdomide is effective in CC-5013, CC-4047, and CC-220-resistant cell lines. It exerts single-agent induction of apoptosis and exhibits remarkable synergy with NSC 34521[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
Clinical Trial
分子量
567.61
Formula
C32H30FN5O4
CAS 号
2259648-80-9
运输条件
Room temperature in continental US; may vary elsewhere.
储存方式
Powder
-20°C
3 years
4°C
2 years
In solvent
-80°C
6 months
-20°C
1 month
溶解性数据
In Vitro:
DMSO : 5 mg/mL (8.81 mM; ultrasonic and warming and heat to 60°C)
Eragidomide (CC-90009) is a first-in-class GSPT1-selective cereblon (CRBN) E3 ligase modulator, acts as a molecular glue. Eragidomide coopts the CRL4CRBN to selectively target GSPT1 for ubiquitination and proteasomal degradation[1][2].
IC50 & Target[1]
Cereblon
体外研究 (In Vitro)
Depletion of GSPT1 by Eragidomide rapidly induces acute myeloid leukemia (AML) apoptosis, reducing leukemia engraftment and leukemia stem cells (LSCs) in large-scale primary patient xenografting of 35 independent AML samples. Eragidomide activity is mediated by multiple layers of signaling networks and pathways within AML blasts and LSCs[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
Clinical Trial
分子量
461.85
Formula
C22H18ClF2N3O4
CAS 号
1860875-51-9
运输条件
Room temperature in continental US; may vary elsewhere.
[1]. Christine Surka, et al. CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells. Blood. 2021 Feb 4;137(5):661-677.
[2]. Joshua D Hansen, et al. CC-90009: A Cereblon E3 Ligase Modulating Drug That Promotes Selective Degradation of GSPT1 for the Treatment of Acute Myeloid Leukemia. J Med Chem. 2021 Feb 25;64(4):1835-1843.
CC-401 is a potent inhibitor of all three forms of JNK with Ki of 25 to 50 nM.
IC50 & Target[1]
JNK
25-50 nM (Ki)
体外研究 (In Vitro)
CC-401 has at least 40-fold selectivity for JNK compared with other related kinases, including p38, extracellular signal-regulated kinase (ERK), inhibitor of κB kinase (IKK2), protein kinase C, Lck, zeta-associated protein of 70 kDa (ZAP70). In cell-based assays, 1 to 5 μM CC-401 provides specific JNK inhibition. CC-401, a small molecule that is a specific inhibitor of all three JNK isoforms. CC-401 competitively binds the ATP binding site in JNK, resulting in inhibition of the phosphorylation of the N-terminal activation domain of the transcription factor c-Jun. The specificity of this inhibitor is tested in vitro using osmotic stress of the HK-2 human tubular epithelial cell line. CC-401 inhibits sorbitol-induced phosphorylation of c-Jun in a dosage-dependent manner. However, CC-401 does not prevent sorbitol-induced phosphorylation of JNK, p38, or ERK[1].
Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.
体内研究 (In Vivo)
The staining of p-JNK is moderately induced in bevazicumab and Oxaliplatin treatments as compared to control, and in the CC-401-treated samples p-cJun content is significantly lower, consistent with effective JNK inhibition. DNA damage is modestly elevated in combined treatments with CC-401[2]. CC-401 treatment from days 7 to 24 slows the progression of proteinuria, which is significantly reduced compared to the no-treatment and vehicle groups at days 14 and 21. However, there is still an increase in the degree of proteinuria at day 21 in CC-401-treated rats compared to proteinuria at day 5. The vehicle and no-treatment groups developed renal impairment at day 24 as shown by an increase in serum creatinine. This is prevented by CC-401 treatment[3].
Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.
Clinical Trial
分子量
388.47
Formula
C22H24N6O
CAS 号
395104-30-0
运输条件
Room temperature in continental US; may vary elsewhere.
储存方式
Please store the product under the recommended conditions in the Certificate of Analysis.
参考文献
[1]. Ma FY, et al. A pathogenic role for c-Jun amino-terminal kinase signaling in renal fibrosis and tubular cell apoptosis. J Am Soc Nephrol. 2007 Feb;18(2):472-84.
[2]. Vasilevskaya IA, et al. Inhibition of JNK Sensitizes Hypoxic Colon Cancer Cells to DNA-Damaging Agents. Clin Cancer Res. 2015 Sep 15;21(18):4143-52.
[3]. Ma FY, et al. Blockade of the c-Jun amino terminal kinase prevents crescent formation and halts established anti-GBM glomerulonephritis in the rat. Lab Invest. 2009 Apr;89(4):470-84.
Cell Assay [1]
Human HK-2 proximal tubular epithelial cells are cultured in DMEM/F12 media supplemented with 10% FCS, 10 ng/mL EGF, and 10 μg/mL bovine pituitary extract. For Western blot studies, cells are seeded into six-well plates and allowed to adhere overnight, and medium is changed to DMEM/F12 supplemented with only 0.5% FCS for 24 h, by which time cells are confluent. CC-401 is prepared in citric acid (pH 5.5) and added to the confluent cells 1 h before the addition of 300 mM sorbitol, and cells are harvested 30 min later using urea-RIPA buffer. Three experiments are performed, each with two replicates per condition. For ELISA experiments, HK-2 cells are seeded into 24-well plates, allowed to adhere overnight, cultured in DMEM/F12 with 0.5% FCS for 24 h, and then incubated with CC-401 or vehicle for 60 min before stimulation with 1 μM Angiotensin II (AngII). Supernatants are harvested 48 h later and assayed for TGF-β1 content using a commercial ELISA kit. Three experiments are performed, each using six replicates per condition[1].
Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.
Animal Administration [2][3]
Mice[2] To assess the efficacy of JNK signaling inhibition by CC-401 in anti-angiogenic and Oxaliplatin combination therapy in a mouse xenograft model, adult (8-10 weeks of age) female severe combined immunodeficient mice (C.B.17 SCID) are used. To generate tumors, HT29 cells (1×106 cells) are injected subcutaneously into the left flank of the mice. When the tumors reached approximately 200 mm3, mice are divided into eight groups (eight mice per group) for treatment with Bevacizumab, Oxaliplatin, CC401, and the appropriate combinations of Bevacizumab, Oxaliplatin and CC-401. Mice in the Bevacizumab treatment group receive 5 mg/kg of Bevacizumab by intraperitoneal injection every 3 days for 21 days. The Oxaliplatin treatment group is injected intraperitoneally with 5 mg/kg Oxaliplatin per week for 2 weeks. The CC-401 treatment group is injected intraperitoneally 25 mg/kg for every 3 days. The combination treatment groups receive Bevacizumab (every 3 days, 5 mg/kg), Oxaliplatin (weekly for 2 weeks, 5 mg/kg), and CC-401 (every 3 days, 25 mg/kg). The control group receive saline intraperitoneally. Tumor volume and body weight are measured every 3 days. Tumor volume is calculated. Tumor growth delay is calculated as the difference in the time for control and treated tumors to grow from 200 to 800 mm3. For tumor growth delay calculations, mice are continued to receive treatments till the tumor volume reached 800 mm3. For immunohistochemistry mice are sacrificed after treatments on day 9 for tumor processing and staining. Rats[3] Female WKY rats (180-220 g) are used. Groups of 9 or 10 rats are immunized by subcutaneous injection of 5 mg of sheep IgG in Freund’s complete adjuvant followed 5 days later (termed day 0) by a tail vein injection of sheep anti-rat GBM serum. In this study, CC-401 (200 mg/kg/b.i.d. by oral gavage) or vehicle (sodium citrate) treatment is initiated in groups of 9 or 10 rats at 7 days after anti-GBM serum administration and continued twice daily thereafter until animals are killed at day 24. Additional groups of rats without treatment are killed at day 7 or day 24 after anti-GBM serum injection as controls. Animals are housed in metabolic cages for 22 hours to collect urine on days 5, 14, and 21. Blood is collected at the time of death. Analysis of serum creatinine and urinary protein are performed.
Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.
参考文献
[1]. Ma FY, et al. A pathogenic role for c-Jun amino-terminal kinase signaling in renal fibrosis and tubular cell apoptosis. J Am Soc Nephrol. 2007 Feb;18(2):472-84.
[2]. Vasilevskaya IA, et al. Inhibition of JNK Sensitizes Hypoxic Colon Cancer Cells to DNA-Damaging Agents. Clin Cancer Res. 2015 Sep 15;21(18):4143-52.
[3]. Ma FY, et al. Blockade of the c-Jun amino terminal kinase prevents crescent formation and halts established anti-GBM glomerulonephritis in the rat. Lab Invest. 2009 Apr;89(4):470-84.
Pulrodemstat Methylbenzenesulfonate Chemical Structure
CAS No. : 2097523-57-2
规格
是否有货
100 mg
询价
250 mg
询价
500 mg
询价
* Please select Quantity before adding items.
Pulrodemstat Methylbenzenesulfonate 的其他形式现货产品:
Pulrodemstat benzenesulfonate
生物活性
CC-90011 Methylbenzenesulfonate is a potent, selective, reversible and orally active inhibitor of lysine specific demethylase-1 (LSD1) with an IC50 of 0.25 nM. CC-90011 Methylbenzenesulfonate is less enzymatic inhibition against LSD2, MOA-A, and MAO-B. CC-90011 Methylbenzenesulfonate induces acute myeloid leukemia (AML) and small cell lung cancer (SCLC) cells differentiation and has potent anticancer activity[1].
IC50 & Target
IC50: 0.25 nM (LSD1)[1]
体外研究 (In Vitro)
CC-90011 (Compound 11) shows potent induction of on-target cellular differentiation marker CD11b in THP-1 cell line with an EC50 of 7 nM, antiproliferative activity in AML kasumi-1 cells with an EC50 of 2 nM[1]. Suppression of GRP is observed with treatment of CC-90011 (4 days) in a dose-dependent manner and at pharmacologically useful concentrations (EC50=3 nM, H209 and 4 nM, H1417). CC-90011 (12 days) treatment of SCLC cells results in potent antiproliferative activity (EC50=6 nM, H1417) that correlated with GRP suppression[1].
Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.
体内研究 (In Vivo)
CC-90011 (5 mg/kg; oral administration; daily; for 30 days; for 30 days) treatment inhibits tumor growth in patient-derived xenograft SCLC models[1]. CC-90011 (once a day; for 4 days) treatment results in robust downregulation of GRP mRNA levels at 2.5 mg/kg and maximum suppression of GRP at 5 mg/kg in a SCLC human tumor xenograft (H1417) mice[1]. After i.v. administration, CC-90011 (Compound 11; 5 mg/kg) has systemic clearance of 32.4 mL/min/kg, elimination half-life of 2 h, and a high volume of distribution of 7.5 L/kg. CC-90011 (Compound 11; 5 mg/kg) is readily absorbed after oral administration with an AUC0-24h of 1.8 μM·h, C/sub>max of 0.36 μM, and oral bioavailability of 32%[1].
Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.
Animal Model:
BALB/c nude mice bearing small cell lung carcinoma (SCLC)[1]
Dosage:
5 mg/kg
Administration:
Oral administration; daily; for 30 days
Result:
Showed a tumor growth inhibition (TGI) of 78% at 5 mg/kg with no body weight loss.
Clinical Trial
分子量
623.67
Formula
C31H31F2N5O5S
CAS 号
2097523-57-2
运输条件
Room temperature in continental US; may vary elsewhere.
储存方式
Please store the product under the recommended conditions in the Certificate of Analysis.
参考文献
[1]. Toufike Kanouni, et al. Discovery of CC-90011: A Potent and Selective Reversible Inhibitor of Lysine Specific Demethylase 1 (LSD1). J Med Chem. 2020 Dec 10;63(23):14522-14529.
Lenalidomide hydrochloride (CC-5013 hydrochloride), a derivative of Thalidomide, acts as molecular glue. Lenalidomide hydrochloride is an orally active immunomodulator. Lenalidomide hydrochloride (CC-5013 hydrochloride) is a ligand of ubiquitin E3 ligase cereblon (CRBN), and it causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. Lenalidomide hydrochloride (CC-5013 hydrochloride) specifically inhibits growth of mature B-cell lymphomas, including multiple myeloma, and induces IL-2 release from T cells[1][2].
IC50 & Target[5]
Cereblon
体外研究 (In Vitro)
Lenalidomide is potent in stimulating T cell proliferation and IFN-γ and IL-2 production. Lenalidomide has been shown to inhibit production of pro inflammatory cytokines TNF-α, IL-1, IL-6, IL-12 and elevate the production of anti-inflammatory cytokine IL-10 from human PBMCs. Lenalidomide downregulates the production of IL-6 directly and also by inhibiting multiple myeloma (MM) cells and bone marrow stromal cells (BMSC) interaction, which augments the apoptosis of myeloma cells[2]. Dose-dependent interaction with the CRBN-DDB1 complex is observed with Thalidomide, Lenalidomide and Pomalidomide, with IC50 values of ~30 μM, ~3 μM and ~3 μM, respectively, These reduced CRBN expression cells (U266-CRBN60 and U266-CRBN75) are less responsive than the parental cells to antiproliferative effects Lenalidomide across a dose-response range of 0.01 to 10 μM[3]. Lenalidomide, a thalidomide analog, functions as a molecular glue between the human E3 ubiquitin ligase cereblon and CKIα is shown to induce the ubiquitination and degradation of this kinase, thus presumably killing leukemic cells by p53 activation[5].
Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.
体内研究 (In Vivo)
The toxicity of Lenalidomide doses up to 15, 22.5, and 45 mg/kg via IV, IP, and PO routes of administration. Limited by solubility in our PBS dosing vehicle, these maximum achievable Lenalidomide doses are well tolerated with the exception of one mouse death (of four total dosed) at the 15 mg/kg IV dose. Notably, no other toxicities are observed in the study at IV doses of 15 mg/kg (n=3) or 10 mg/kg (n=45) or at any other dose level through IV, IP, and PO routes[4].
Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.
Clinical Trial
分子量
295.72
Formula
C13H14ClN3O3
CAS 号
1243329-97-6
中文名称
来那度胺盐酸盐；雷那度胺盐酸盐
运输条件
Room temperature in continental US; may vary elsewhere.
储存方式
Please store the product under the recommended conditions in the Certificate of Analysis.
参考文献
[1]. Omran A, et al. Effects of MRP8, LPS, and lenalidomide on the expressions of TNF-α , brain-enriched, and inflammation-related microRNAs in the primary astrocyte culture. ScientificWorldJournal. 2013 Sep 21;2013:208309.
[2]. Krönke J, et al. Lenalidomide induces degradation of IKZF1 and IKZF3. Oncoimmunology. 2014 Jul 3;3(7):e941742.
[3]. Minzel W, et al. Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models. Cell. 2018 Sep 20;175(1):171-185.e25.
[4]. Kotla V, et al. Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol. 2009 Aug 12;2:36.
[5]. Lopez-Girona A, et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia. 2012 Nov;26(11):2326-35.
[6]. Rozewski DM, et al. Pharmacokinetics and tissue disposition of lenalidomide in mice. AAPS J. 2012 Dec;14(4):872-82.
Cell Assay [3]
Cell lines NCI-H929 and U266, and DF15 cells are grown in RPMI-I640 medium containing 10% (V/V) heat-inactivated fetal bovine serum supplemented with 2 mM glutamine. To produce Lenalidomide resistant cell lines, NCI-H929 cells are treated continuously (fresh Lenalidomide is added every 3-4 days) with control (final 0.1% DMSO) or low-dose Lenalidomide (1 μM) for 2 months until the proliferation of cells is no longer inhibited by Lenalidomide (1 μM), as determined by cell viability (Vi-cell XR cell viability analyzer), cell proliferation by flow cytometry and cell cycle analysis (propidium iodide staining). After acquisition of resistance to 1 μM, the resistant H929 cell lines are treated with Lenalidomide (10 μM) for a further 4 months. After this period of time, the cell cultures achieved fully establish resistance up to high-dose Lenalidomide (30 μM). Prior to the experiments described here, H929 Lenalidomide-resistant cells are taken out of culture with compounds for 5-7 days before use[3].
Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.
Animal Administration [4]
Mice[4] Imprinting control region (ICR) mice 8-10 weeks of age are used. Lenalidomide is incompletely soluble at 3.5 mg/mL and above in PBS containing 1% HCl, as visible particulates remained after thorough mixing. Therefore 3 mg/mL is selected as the maximum dosing solution concentration (with no visible particulates). Single, individual mice are initially dosed with 3, 10, or 15 mg/kg IV; 4.5, 15, or 22.5 mg/kg IP; and 9, 30, or 45 mg/kg PO. Additional mice (n=4) are then evaluated at the maximum dose achievable by volume and solubility of Lenalidomide in the dosing solution. All mice are monitored closely for 1 h and re-evaluated for toxicities 3, 6, and 24 h postdose.
Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.
参考文献
[1]. Omran A, et al. Effects of MRP8, LPS, and lenalidomide on the expressions of TNF-α , brain-enriched, and inflammation-related microRNAs in the primary astrocyte culture. ScientificWorldJournal. 2013 Sep 21;2013:208309.
[2]. Krönke J, et al. Lenalidomide induces degradation of IKZF1 and IKZF3. Oncoimmunology. 2014 Jul 3;3(7):e941742.
[3]. Minzel W, et al. Small Molecules Co-targeting CKIα and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models. Cell. 2018 Sep 20;175(1):171-185.e25.
[4]. Kotla V, et al. Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol. 2009 Aug 12;2:36.
[5]. Lopez-Girona A, et al. Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia. 2012 Nov;26(11):2326-35.
[6]. Rozewski DM, et al. Pharmacokinetics and tissue disposition of lenalidomide in mice. AAPS J. 2012 Dec;14(4):872-82.
Pulrodemstat (CC-90011) is a potent, selective, reversible and orally active inhibitor of lysine specific demethylase-1 (LSD1) with an IC50 of 0.25 nM. Pulrodemstat is less enzymatic inhibition against LSD2, MOA-A, and MAO-B. Pulrodemstat induces acute myeloid leukemia (AML) and small cell lung cancer (SCLC) cells differentiation and has potent anticancer activity[1].
IC50 & Target
IC50: 0.25 nM (LSD1)[1]
体外研究 (In Vitro)
Pulrodemstat (CC-90011, Compound 11) shows potent induction of on-target cellular differentiation marker CD11b in THP-1 cell line with an EC50 of 7 nM, antiproliferative activity in AML kasumi-1 cells with an EC50 of 2 nM[1]. Suppression of GRP is observed with treatment of Pulrodemstat (4 days) in a dose-dependent manner and at pharmacologically useful concentrations (EC50=3 nM, H209 and 4 nM, H1417). Pulrodemstat (12 days) treatment of SCLC cells results in potent antiproliferative activity (EC50=6 nM, H1417) that correlated with GRP suppression[1].
Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.
体内研究 (In Vivo)
Pulrodemstat (CC-90011; 5 mg/kg; oral administration; daily; for 30 days; for 30 days) treatment inhibits tumor growth in patient-derived xenograft SCLC models[1]. Pulrodemstat (once a day; for 4 days) treatment results in robust downregulation of GRP mRNA levels at 2.5 mg/kg and maximum suppression of GRP at 5 mg/kg in a SCLC human tumor xenograft (H1417) mice[1]. After i.v. administration, Pulrodemstat (Compound 11; 5 mg/kg) has systemic clearance of 32.4 mL/min/kg, elimination half-life of 2 h, and a high volume of distribution of 7.5 L/kg. Pulrodemstat (Compound 11; 5 mg/kg) is readily absorbed after oral administration with an AUC0-24h of 1.8 μM·h, C/sub>max of 0.36 μM, and oral bioavailability of 32%[1].
Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.
Animal Model:
BALB/c nude mice bearing small cell lung carcinoma (SCLC)[1]
Dosage:
5 mg/kg
Administration:
Oral administration; daily; for 30 days
Result:
Showed a tumor growth inhibition (TGI) of 78% at 5 mg/kg with no body weight loss.
分子量
451.47
Formula
C24H23F2N5O2
CAS 号
1821307-10-1
运输条件
Room temperature in continental US; may vary elsewhere.
储存方式
Please store the product under the recommended conditions in the Certificate of Analysis.
参考文献
[1]. Toufike Kanouni, et al. Discovery of CC-90011: A Potent and Selective Reversible Inhibitor of Lysine Specific Demethylase 1 (LSD1). J Med Chem. 2020 Dec 10;63(23):14522-14529.
CC-90011 benzenesulfonate is a potent, selective, reversible and orally active inhibitor of lysine specific demethylase-1 (LSD1) with an IC50 of 0.25 nM. CC-90011 benzenesulfonate is less enzymatic inhibition against LSD2, MOA-A, and MAO-B. CC-90011 benzenesulfonate induces acute myeloid leukemia (AML) and small cell lung cancer (SCLC) cells differentiation and has potent anticancer activity[1].
IC50 & Target
IC50: 0.25 nM (LSD1)[1]
体外研究 (In Vitro)
CC-90011 (Compound 11) shows potent induction of on-target cellular differentiation marker CD11b in THP-1 cell line with an EC50 of 7 nM, antiproliferative activity in AML kasumi-1 cells with an EC50 of 2 nM[1]. Suppression of GRP is observed with treatment of CC-90011 (4 days) in a dose-dependent manner and at pharmacologically useful concentrations (EC50=3 nM, H209 and 4 nM, H1417). CC-90011 (12 days) treatment of SCLC cells results in potent antiproliferative activity (EC50=6 nM, H1417) that correlated with GRP suppression[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
体内研究 (In Vivo)
CC-90011 (5 mg/kg; oral administration; daily; for 30 days; for 30 days) treatment inhibits tumor growth in patient-derived xenograft SCLC models[1]. CC-90011 (once a day; for 4 days) treatment results in robust downregulation of GRP mRNA levels at 2.5 mg/kg and maximum suppression of GRP at 5 mg/kg in a SCLC human tumor xenograft (H1417) mice[1]. After i.v. administration, CC-90011 (Compound 11; 5 mg/kg) has systemic clearance of 32.4 mL/min/kg, elimination half-life of 2 h, and a high volume of distribution of 7.5 L/kg. CC-90011 (Compound 11; 5 mg/kg) is readily absorbed after oral administration with an AUC0-24h of 1.8 μM·h, C/sub>max of 0.36 μM, and oral bioavailability of 32%[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
Animal Model:
BALB/c nude mice bearing small cell lung carcinoma (SCLC)[1]
Dosage:
5 mg/kg
Administration:
Oral administration; daily; for 30 days
Result:
Showed a tumor growth inhibition (TGI) of 78% at 5 mg/kg with no body weight loss.
Clinical Trial
分子量
609.64
Formula
C30H29F2N5O5S
CAS 号
2097523-60-7
运输条件
Room temperature in continental US; may vary elsewhere.
将 2 g 磺丁基醚 β-环糊精加入 5 mL 生理盐水中，再用生理盐水定容至 10 mL，完全溶解，澄清透明
*以上所有助溶剂都可在 上海金畔生物科技有限公司 网站选购。
参考文献
[1]. Toufike Kanouni, et al. Discovery of CC-90011: A Potent and Selective Reversible Inhibitor of Lysine Specific Demethylase 1 (LSD1). J Med Chem. 2020 Dec 10;63(23):14522-14529.
[1]. CELGENE QUANTICEL RESEARCH, INC. PROCESS FOR THE PREPARATION OF BROMODOMAIN INHIBITOR. Patent. WO2020023438.
[2]. V. Moreno, et al. CC-90010, a reversible, oral bromodomain and extra-terminal (BET) inhibitor in patients (Pts) with advanced solid tumours (STs) and relapsed/refractory (R/R) non-Hodgkin lymphoma: Updated results of a phase I study.
Avadomide (CC 122) is an orally active cereblon modulator. Avadomide modulates cereblon E3 ligase activity and induces apoptosis of diffuse large B-cell lymphoma (DLBCL) cell lines. Avadomide exhibits potent antitumor and immunomodulatory activities[1][2].
体外研究 (In Vitro)
Avadomide inhibits proliferation and induces apoptosis in ABC and GCB DLBCL. In DLBCL cell lines, Avadomide-induced degradation or short hairpin RNA-mediated knockdown of Aiolos and Ikaros correlates with increased transcription of IFN-stimulated genes independent of IFN-α, -β, and -γ production and/or secretion and results in apoptosis in both activated B-cell (ABC) and germinal center B-cell DLBCL.[1]
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
体内研究 (In Vivo)
Treatment of female CB-17 SCID mice with Avadomide (CC122) at 3 or 30 mg/kg once daily significantly decreased tumor growth in OCI-LY10 ABC-DLBCL (P = .028 and P < .001, respectively) and WSU-DLCL2 GCB-DLBCL derived xenograft models (P < .01) compared with the vehicle control. In a separate study, we assessed the ability of Avadomide (CC122) to promote degradation of Ikaros and Aiolos in vivo. In the 21-day efficacy study of WSU-DLCL2 xenograft transplanted mice, tumors were excised 1, 6, or 24 hours post final dosing. Aiolos and Ikaros expression was interrogated through immunohistochemistry (IHC) and was found to be decreased 64% and 30%, respectively, compared with vehicle within 1 hour of treatment, with a maximal reduction of 94% and 69%, respectively, observed at 6 hours. Aiolos and Ikaros levels partially recovered 24 hours postdosing with protein level within 20% and 34% of vehicle, respectively. The 24-hour postdose Aiolos and Ikaros expression represents the trough compound level following multiple doses of Avadomide (CC122). When the 1-hour time point is compared with the 24-hour postdose time point, there is a significant reduction in Aiolos but not Ikaros expression; however, at the 6-hour time point, both transcription factors are significantly different from the 24-hour time point. Taken together, these data reveal that Avadomide (CC122) inhibited DLBCL tumor growth in vivo and that this activity was associated with the degradation of Aiolos and Ikaros in both ABC- and GCB-DLBCL xenograft models.[1]
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
Clinical Trial
分子量
286.29
Formula
C14H14N4O3
CAS 号
1015474-32-4
运输条件
Room temperature in continental US; may vary elsewhere.
[1]. Rasco DW, et al. A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies. Clin Cancer Res. 2019 Jan 1;25(1):90-98.
[2]. Hagner, P.R.et al.CC-122, a pleiotropic pathway modifier, mimics an IFN response and has antitumor activity in DLBCL.Blood.Aug 6;126(6):779-89.
Animal Administration
Female SCID mice (CB17/Icr-Prkdcscid, Charles River) were 8 weeks old, with body weights ranging from 15.0 to 23.2 g, on day 1 of these studies. Each SCID mouse was injected subcutaneously in the right flank with 5×106 OCI-LY10 cells (0.2 ml cell suspension). Tumors were calipered in two dimensions to monitor growth as their mean volume approached 100–150 mm3 . Fourteen days (WSU-DLCL2) or twenty-one days (OCI-LY10) after tumor cell implantation, mice were sorted into treatment groups (n=10/group). Tumors were callipered twice weekly during the study. Avadomide (CC122) was suspended in 0.5% carboxymethyl cellulose: 0.25% Tween-80 in de-ionized water. Vehicle and Avadomide (CC122) were each administered via oral gavage (p.o.) once daily for twenty-eight days (qd x28). [1]
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
参考文献
[1]. Rasco DW, et al. A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies. Clin Cancer Res. 2019 Jan 1;25(1):90-98.
[2]. Hagner, P.R.et al.CC-122, a pleiotropic pathway modifier, mimics an IFN response and has antitumor activity in DLBCL.Blood.Aug 6;126(6):779-89.
CC-401 hydrochloride is a potent inhibitor of all three forms of JNK with Ki of 25 to 50 nM.
IC50 & Target[1]
JNK
25-50 nM (Ki)
体外研究 (In Vitro)
CC-401 has at least 40-fold selectivity for JNK compared with other related kinases, including p38, extracellular signal-regulated kinase (ERK), inhibitor of κB kinase (IKK2), protein kinase C, Lck, zeta-associated protein of 70 kDa (ZAP70). In cell-based assays, 1 to 5 μM CC-401 provides specific JNK inhibition. CC-401, a small molecule that is a specific inhibitor of all three JNK isoforms. CC-401 competitively binds the ATP binding site in JNK, resulting in inhibition of the phosphorylation of the N-terminal activation domain of the transcription factor c-Jun. The specificity of this inhibitor is tested in vitro using osmotic stress of the HK-2 human tubular epithelial cell line. CC-401 inhibits sorbitol-induced phosphorylation of c-Jun in a dosage-dependent manner. However, CC-401 does not prevent sorbitol-induced phosphorylation of JNK, p38, or ERK[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
体内研究 (In Vivo)
The staining of p-JNK is moderately induced in bevazicumab and Oxaliplatin treatments as compared to control, and in the CC-401-treated samples p-cJun content is significantly lower, consistent with effective JNK inhibition. DNA damage is modestly elevated in combined treatments with CC-401[2]. CC-401 treatment from days 7 to 24 slows the progression of proteinuria, which is significantly reduced compared to the no-treatment and vehicle groups at days 14 and 21. However, there is still an increase in the degree of proteinuria at day 21 in CC-401-treated rats compared to proteinuria at day 5. The vehicle and no-treatment groups developed renal impairment at day 24 as shown by an increase in serum creatinine. This is prevented by CC-401 treatment[3].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
Clinical Trial
分子量
424.93
Formula
C22H25ClN6O
CAS 号
1438391-30-0
运输条件
Room temperature in continental US; may vary elsewhere.
[1]. Ma FY, et al. A pathogenic role for c-Jun amino-terminal kinase signaling in renal fibrosis and tubular cell apoptosis. J Am Soc Nephrol. 2007 Feb;18(2):472-84.
[2]. Vasilevskaya IA, et al. Inhibition of JNK Sensitizes Hypoxic Colon Cancer Cells to DNA-Damaging Agents. Clin Cancer Res. 2015 Sep 15;21(18):4143-52.
[3]. Ma FY, et al. Blockade of the c-Jun amino terminal kinase prevents crescent formation and halts established anti-GBM glomerulonephritis in the rat. Lab Invest. 2009 Apr;89(4):470-84.
Cell Assay [1]
Human HK-2 proximal tubular epithelial cells are cultured in DMEM/F12 media supplemented with 10% FCS, 10 ng/mL EGF, and 10 μg/mL bovine pituitary extract. For Western blot studies, cells are seeded into six-well plates and allowed to adhere overnight, and medium is changed to DMEM/F12 supplemented with only 0.5% FCS for 24 h, by which time cells are confluent. CC-401 is prepared in citric acid (pH 5.5) and added to the confluent cells 1 h before the addition of 300 mM sorbitol, and cells are harvested 30 min later using urea-RIPA buffer. Three experiments are performed, each with two replicates per condition. For ELISA experiments, HK-2 cells are seeded into 24-well plates, allowed to adhere overnight, cultured in DMEM/F12 with 0.5% FCS for 24 h, and then incubated with CC-401 or vehicle for 60 min before stimulation with 1 μM Angiotensin II (AngII). Supernatants are harvested 48 h later and assayed for TGF-β1 content using a commercial ELISA kit. Three experiments are performed, each using six replicates per condition[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
Animal Administration [2][3]
Mice[2] To assess the efficacy of JNK signaling inhibition by CC-401 in anti-angiogenic and Oxaliplatin combination therapy in a mouse xenograft model, adult (8-10 weeks of age) female severe combined immunodeficient mice (C.B.17 SCID) are used. To generate tumors, HT29 cells (1×106 cells) are injected subcutaneously into the left flank of the mice. When the tumors reached approximately 200 mm3, mice are divided into eight groups (eight mice per group) for treatment with Bevacizumab, Oxaliplatin, CC401, and the appropriate combinations of Bevacizumab, Oxaliplatin and CC-401. Mice in the Bevacizumab treatment group receive 5 mg/kg of Bevacizumab by intraperitoneal injection every 3 days for 21 days. The Oxaliplatin treatment group is injected intraperitoneally with 5 mg/kg Oxaliplatin per week for 2 weeks. The CC-401 treatment group is injected intraperitoneally 25 mg/kg for every 3 days. The combination treatment groups receive Bevacizumab (every 3 days, 5 mg/kg), Oxaliplatin (weekly for 2 weeks, 5 mg/kg), and CC-401 (every 3 days, 25 mg/kg). The control group receive saline intraperitoneally. Tumor volume and body weight are measured every 3 days. Tumor volume is calculated. Tumor growth delay is calculated as the difference in the time for control and treated tumors to grow from 200 to 800 mm3. For tumor growth delay calculations, mice are continued to receive treatments till the tumor volume reached 800 mm3. For immunohistochemistry mice are sacrificed after treatments on day 9 for tumor processing and staining. Rats[3] Female WKY rats (180-220 g) are used. Groups of 9 or 10 rats are immunized by subcutaneous injection of 5 mg of sheep IgG in Freund’s complete adjuvant followed 5 days later (termed day 0) by a tail vein injection of sheep anti-rat GBM serum. In this study, CC-401 (200 mg/kg/b.i.d. by oral gavage) or vehicle (sodium citrate) treatment is initiated in groups of 9 or 10 rats at 7 days after anti-GBM serum administration and continued twice daily thereafter until animals are killed at day 24. Additional groups of rats without treatment are killed at day 7 or day 24 after anti-GBM serum injection as controls. Animals are housed in metabolic cages for 22 hours to collect urine on days 5, 14, and 21. Blood is collected at the time of death. Analysis of serum creatinine and urinary protein are performed.
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
参考文献
[1]. Ma FY, et al. A pathogenic role for c-Jun amino-terminal kinase signaling in renal fibrosis and tubular cell apoptosis. J Am Soc Nephrol. 2007 Feb;18(2):472-84.
[2]. Vasilevskaya IA, et al. Inhibition of JNK Sensitizes Hypoxic Colon Cancer Cells to DNA-Damaging Agents. Clin Cancer Res. 2015 Sep 15;21(18):4143-52.
[3]. Ma FY, et al. Blockade of the c-Jun amino terminal kinase prevents crescent formation and halts established anti-GBM glomerulonephritis in the rat. Lab Invest. 2009 Apr;89(4):470-84.
Onatasertib (CC-223) is a potent, selective, and orally bioavailable inhibitor of mTOR kinase, with an IC50 value for mTOR kinase of 16 nM. Onatasertib inhibits both mTORC1 and mTORC2.
IC50 & Target[1]
mTOR
16 nM (IC50)
mTORC1
mTORC2
DNA-PK
0.84 μM (IC50)
PI3K-α
4 μM (IC50)
体外研究 (In Vitro)
Onatasertib is a potent, selective, and orally bioavailable inhibitor of mTOR kinase, demonstrating inhibition of mTORC1 (pS6RP and p4EBP1) and mTORC2 [pAKT(S473)] in cellular systems. Onatasertib is selective for mTOR kinase with >200-fold selectivity over the related PI3K-α (IC50=4.0 μM). Of the PI3K related kinases tested, Onatasertib shows no significant inhibition of ATR or SMG1 and inhibits DNA-PK with an IC50 value of 0.84 μM. When screened in a single-point assay against a commercially available panel of 246 kinases, only three kinases other than mTOR are inhibited >80% at 10 μM by Onatasertib. Upon follow-up IC50 value determination, only two are inhibited by Onatasertib with IC50 values below 1 μM; FLT4 (0.651 μM) and cFMS (0.028 μM). The exquisite kinase selectivity of Onatasertib is confirmed upon evaluation in cellular systems using ActivX KiNavtiv profiling. Other than mTOR kinase, no kinase target is identified when HCT 116 or A549 cells are treated for 1 hour with 1 μM Onatasertib and assayed for kinase activity. Onatasertib shows a concentration-dependent reduction in each marker, with IC50 values of 31±2 nM for pS6RP, 405±47 nM for p4EBP1, and 11±10 nM for pAKT(S473) in western blot analysis. Inhibition of these pathway biomarkers is investigated in additional cell types from a variety of tissue origins. Onatasertib inhibits both mTORC1 (S6RP and 4EBP1) and mTORC2 [AKT(S473)] markers across the panel with IC50 ranges of 27 to 184 nM for pS6RP, 120 to 1,050 nM for p4EBP1 and 11 to 150 nM for pAKT(S473) [1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
体内研究 (In Vivo)
The antitumor activity of Onatasertib in the PC-3 xenograft model is determined using a number of dosing paradigms. Onatasertib significantly inhibits PC-3 tumor growth in a dose- and schedule-dependent manner. Dosing at 10 or 25 mg/kg, once daily, results in 46% (P<0.001) and 87% (P<0.001) reduction in tumor volume, respectively. Similar dose dependency is observed with twice-daily dosing at 5 or 10 mg/kg, corresponding to 65% (P<0.001) and 80% (P<0.001) tumor volume reductions. All dose levels are tolerated in the once-daily and twice-daily dosing studies, with only the 25 mg/kg/d group showing any significant body weight loss. These mice lost approximately 10% of their initial body weight after 3 weeks of dosing[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
Clinical Trial
分子量
397.47
Formula
C21H27N5O3
CAS 号
1228013-30-6
运输条件
Room temperature in continental US; may vary elsewhere.
[1]. Mortensen DS, et al. CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and In Vivo Characterization. Mol Cancer Ther. 2015 Jun;14(6):1295-305.
Kinase Assay [1]
Counter screen against 246 protein kinases is outsourced and completed at a fixed CC-223 concentration (10 μM). Follow-up IC50 value determinations for ephrin type-B receptor 3 kinase (EPHB3), colony stimulating factor 1 receptor tyrosine kinase (CSF1R or cFMS), and FMS-related tyrosine kinase 4 (FLT4) are outsourced to Invitrogen[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
Cell Assay [1]
For other cell panel proliferation assays, CC-223 (1 nM, 100 nM and 1 μM) is spotted via an acoustic dispenser (EDC ATS-100) into an empty 384-well plate. Cells are diluted to desired densities and added directly to the compound-spotted plates. Cells are allowed to grow for 72 hours. Viability is assessed via Cell Titer-Glo. All data are normalized and represented as a percentage of the DMSO-treated cells. Results are then expressed as GI50 and/or IC50 values[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
Animal Administration [1]
Mice[1] Female 6- to 8-weeks-old CB17 SCID mice are inoculated s.c. with 2×106 PC-3 cells. When tumors reach approximately 125 mm3, mice are randomized and treated once daily, twice daily, or every 2 days orally with vehicle or various doses of CC-223, at a dose volume of 5 mL/kg. The twice-daily doses are administered with a 10 hours separation between the morning and evening doses. Tumor volumes are determined before the initiation of treatment and are considered as the starting volumes. Tumors are measured twice a week for the duration of the study. The long and short axes of each tumor are measured using a digital caliper in millimeters. The tumor volumes are calculated. The tumor volumes are expressed in cubic millimeters (mm3).
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
参考文献
[1]. Mortensen DS, et al. CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and In Vivo Characterization. Mol Cancer Ther. 2015 Jun;14(6):1295-305.
