WEE1-IN-5 (Debio 0123) is a potent, orally available and highly specific WEE1 inhibitor with an IC50 in the low nanomolar range. WEE1-IN-5 inhibits phospho-CDC2 which translated into an increase in DNA damage and premature entry into mitosis. WEE1-IN-5 increases antitumoral activity of Carboplatin in vivo where neither agent was active alone[1].
IC50 & Target
IC50: 0.8 nM (WEE1)[1]
体外研究 (In Vitro)
WEE1-IN-5 exhibits an EC50 of 188 nM in pCDC2 and an IC50 shift for CYP3A4/5[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)
WEE1-IN-5 (5mg/kg for PO; 1 mg/kg for IV; single dosage) exhibits a CL of 14 mL/min/kg, an AUCint 1324 h·ng/mL and bioavailability of 35% in SD rats[1].
Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.
分子量
511.45
Formula
C26H28Cl2N6O
CAS 号
2243882-74-6
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]. H. Gelderblom, et al. 601TiP First-in-human phase I study of a novel oral Wee1 inhibitor (Debio 0123) in combination with carboplatin in patients with advanced solid tumours. Ann Oncol. 2020 Sep; 31: S501-S502.
Debio 0617B, a multi-kinase inhibitor, reduces maintenance and self-renewal of primary human AML CD34+ stem/progenitor cells. Debio 0617B has a unique profile targeting key kinases upstream of STAT3/STAT5 signaling such as JAK, SRC, ABL, and class III/V receptor tyrosine kinases (TKs). Debio 0617B has documented efficacy in STAT3-driven solid tumors[1].
分子量
581.98
Formula
C28H23ClF3N7O2
CAS 号
1332329-27-7
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]. Maximilien Murone, et al. The Multi-kinase Inhibitor Debio 0617B Reduces Maintenance and Self-renewal of Primary Human AML CD34+ Stem/Progenitor Cells. Mol Cancer Ther. 2017 Aug;16(8):1497-1510.
Debio 0617B, a multi-kinase inhibitor, reduces maintenance and self-renewal of primary human AML CD34+ stem/progenitor cells. Debio 0617B has a unique profile targeting key kinases upstream of STAT3/STAT5 signaling such as JAK, SRC, ABL, and class III/V receptor tyrosine kinases (TKs). Debio 0617B has documented efficacy in STAT3-driven solid tumors[1].
分子量
581.98
Formula
C28H23ClF3N7O2
CAS 号
1332329-27-7
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]. Maximilien Murone, et al. The Multi-kinase Inhibitor Debio 0617B Reduces Maintenance and Self-renewal of Primary Human AML CD34+ Stem/Progenitor Cells. Mol Cancer Ther. 2017 Aug;16(8):1497-1510.
Debio 0617B, a multi-kinase inhibitor, reduces maintenance and self-renewal of primary human AML CD34+ stem/progenitor cells. Debio 0617B has a unique profile targeting key kinases upstream of STAT3/STAT5 signaling such as JAK, SRC, ABL, and class III/V receptor tyrosine kinases (TKs). Debio 0617B has documented efficacy in STAT3-driven solid tumors[1].
分子量
581.98
Formula
C28H23ClF3N7O2
CAS 号
1332329-27-7
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]. Maximilien Murone, et al. The Multi-kinase Inhibitor Debio 0617B Reduces Maintenance and Self-renewal of Primary Human AML CD34+ Stem/Progenitor Cells. Mol Cancer Ther. 2017 Aug;16(8):1497-1510.
Zoligratinib (Debio 1347) is an orally available and selective FGFR inhibitor with IC50s of 9.3, 7.6, and 22 nM for FGFR1, FGFR2, FGFR3, and FGFR4, respectively.
IC50 & Target[1]
FGFR1
9.3 nM (IC50)
FGFR2
7.6 nM (IC50)
FGFR3
22 nM (IC50)
FGFR4
290 nM (IC50)
体外研究 (In Vitro)
Zoligratinib is well balanced in cellular antiproliferative activity against SNU-16 and stability in human liver microsome. The selectivity of 8 to inhibit FGFR over KDR is suggested to be caused by the difference in the interaction with M535 in FGFR1 and L889 in KDR[1]. The IC50 of Zoligratinib is 29 nM for FGF-dependent proliferation and 780 nM for VEGF-dependent proliferation[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.
体内研究 (In Vivo)
Zoligratinib treatment shows a dose-dependent tumor regression (tumor growth inhibition (TGI)=106% at 30 mg/kg and 147% at 100 mg/kg) without apparent body weight loss. Zoligratinib treatment also shows significant in vivo efficacy in xenograft mice models with FGFR genetic alterations, such as KG1 (leukemia, FGFR1OP-FGFR1 fusion), MFE280 (endometrial cancer, FGFR2 S252W mutation), UM-UC-14 (bladder cancer, FGFR3 S249C mutation), and RT112/84 (bladder cancer, FGFR3-TACC3 fusion)[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
356.38
Formula
C20H16N6O
CAS 号
1265229-25-1
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 : 25 mg/mL (70.15 mM; ultrasonic and warming and heat to 50°C)
[1]. Nakanishi Y, et al. The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitor. Mol Cancer Ther. 2014 Nov;13(11):2547-58.
[2]. Nakanishi Y, et al. Mechanism of Oncogenic Signal Activation by the Novel Fusion Kinase FGFR3-BAIAP2L1. Mol Cancer Ther. 2015 Mar;14(3):704-12.
[3]. Nakanishi Y, et al. ERK Signal Suppression and Sensitivity to CH5183284/Debio 1347, a Selective FGFR Inhibitor. Mol Cancer Ther. 2015 Dec;14(12):2831-9.
Cell Assay [1]
The cell lines are added to the wells of 96-well plates containing 0.076−10,000 nM tested compounds (CH5183284) and incubated at 37°C. After 4 days’ incubation, Cell Counting Kit-8 solution is added, and after incubation for several more hours, absorbance at 450 nm is measured. The antiproliferative activity is calculated using the formula (1-T/C) × 100 (%), where T and C represent absorbance at 450 nm of the cells treated with drugs (T) and that of untreated control cells (C)[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][2]
Rats: Male Wistar rats (340-390 g) implanted with a telemetry transmitter are used for the assessment of effects on blood pressure (BP). Vehicle (0.5% carmellose sodium, 0.5% polysorbate 20, and 0.9% benzyl alcohol in purified water) or CH5183284/Debio 1347 (10 and 30 mg/kg) are administered by oral gavage once a day for 4 consecutive days. Data for blood pressure are automatically analyzed and continuously recorded at 5-minute intervals[2].
Mice: The in vivo efficacy is evaluated in mice bearing an SNU-16 xenograft. CH5183284 is orally administered once daily for 11 days, and the body weight of mice and the volume of the tumors are measured twice a week[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]. Nakanishi Y, et al. The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitor. Mol Cancer Ther. 2014 Nov;13(11):2547-58.
[2]. Nakanishi Y, et al. Mechanism of Oncogenic Signal Activation by the Novel Fusion Kinase FGFR3-BAIAP2L1. Mol Cancer Ther. 2015 Mar;14(3):704-12.
[3]. Nakanishi Y, et al. ERK Signal Suppression and Sensitivity to CH5183284/Debio 1347, a Selective FGFR Inhibitor. Mol Cancer Ther. 2015 Dec;14(12):2831-9.
Debio 0932 (CUDC-305) is an orally active HSP90 inhibitor, with IC50s of 100 and 103 nM for HSP90α and HSP90β, respectively[1].
IC50 & Target[1]
HSP90α
100 nM (IC50)
HSP90β
103 nM (IC50)
体外研究 (In Vitro)
Debio 0932 is an orally active HSP90 inhibitor, with IC50s of 100 and 103 nM for HSP90α and HSP90β, respectively. Debio 0932 (CUDC-305) binds to the tumor HSP90 complex with a mean IC50 of 48.8 nM. Debio 0932 (1 μM) promotes degradation of multiple HSP90 client proteins in cancer cell lines. Debio 0932 also shows inhibitory activities against the proliferation of 40 cancer cell lines (containing 34 solid and 6 hematologic tumor-derived lines) with an IC50 ranging from 40 to 900 nM (mean IC50, 220 nM)[1]. Debio 0932 strongly binds to cancer-derived HSP90 complex with an IC50 of 61.2 nM in H1975 cells and 74.2 nM in H1993 cells, respectively. Debio 0932 (CUDC-305, 1 μM) durably induces oncoprotein degradation in NSCLC cell lines with mutations that can confer resistance to erlotinib[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.
体内研究 (In Vivo)
Debio 0932 (CUDC-305, 30 mg/kg, p.o.) exhibits favorable pharmacokinetic profiles in tumor-bearing nude mice. Debio 0932 (160 mg/kg, p.o.) causes degradation of HSP90 client proteins, suppresses tumor growth, and also prolongs survival in various animal models of U87MG glioblastoma. Debio 0932 (40, 80, or 160 mg/kg, p.o.) also dose-dependently inhibits tumor growth in the U87MG s.c. tumor model by every-other-day (q2d) dosing[1]. Debio 0932 (80 mg/kg, p.o.) significantly alleviates psoriasis by day 11 and decreases epidermal thickness in psoriasis xenograft transplantation model[2]. Debio 0932 (CUDC-305) is able to cross the blood-brain barrier. Debio 0932 (80, 120, and 160 mg/kg, p.o.) shows dose-dependent inhibition of tumor growth in the H1975 subcutaneous tumor model. Debio 0932 (160 mg/kg, p.o.) also promotes antitumor activity in the erlotinib-resistant H1975 subcutaneous tumor model[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
442.58
Formula
C22H30N6O2S
CAS 号
1061318-81-7
运输条件
Room temperature in continental US; may vary elsewhere.
[1]. Bao R, et al. CUDC-305, a novel synthetic HSP90 inhibitor with unique pharmacologic properties for cancer therapy. Clin Cancer Res. 2009 Jun 15;15(12):4046-57.
[2]. Stenderup K, et al. Debio 0932, a new oral Hsp90 inhibitor, alleviates psoriasis in a xenograft transplantation model. Acta Derm Venereol. 2014 Nov;94(6):672-6.
[3]. Bao R, et al. Targeting heat shock protein 90 with CUDC-305 overcomes erlotinib resistance in non-small cell lung cancer. Mol Cancer Ther. 2009 Dec;8(12):3296-306.
Cell Assay [1]
Human cancer cell lines are plated at 5,000 to 10,000 per well in 96-well plates with culture medium. The cells are then incubated with compounds (Debio 0932) at various concentrations for 120 h. Growth inhibition is assessed by ATP content assay using the ATPlite kit. Briefly, a 25-μL cell lysis solution is added to the 50-μL phenol red-free culture medium per well to lyse cells and stabilize ATP. Then 25-μL substrate solutions are added to the wells, and subsequently, luminescence is measured with a TopCount liquid scintillation analyzer. Values are expressed as a percentage relative to those obtained in untreated controls. IC50 values are calculated using PRISM software with sigmoidal dose-response curve fitting[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]
When tumors are established after implantation, animals with proper tumor size are randomly assigned into different groups. Debio 0932 is formulated in 30% Captisol and delivered by oral gavage based on the body weight of each individual animal. The control group is treated with vehicle (30% Captisol) using the same dosing paradigm. In combination studies, paclitaxel or camptothecin-11 is diluted in 0.9% normal saline and injected i.p. twice weekly[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]. Bao R, et al. CUDC-305, a novel synthetic HSP90 inhibitor with unique pharmacologic properties for cancer therapy. Clin Cancer Res. 2009 Jun 15;15(12):4046-57.
[2]. Stenderup K, et al. Debio 0932, a new oral Hsp90 inhibitor, alleviates psoriasis in a xenograft transplantation model. Acta Derm Venereol. 2014 Nov;94(6):672-6.
[3]. Bao R, et al. Targeting heat shock protein 90 with CUDC-305 overcomes erlotinib resistance in non-small cell lung cancer. Mol Cancer Ther. 2009 Dec;8(12):3296-306.
Ki16425 (Debio 0719) is a subtype-selective, competitive antagonist of the EDG-family receptors, LPA1 and LPA3 with Kis of 0.34 μM and 0.93 μM, respectively. Ki16425 (Debio 0719) reduces the LPA-induced activation of p42/p44 MAPK[1][2]. Ki16425 can also inhibit LPA-induced dephosphorylation of Yes-associated protein (YAP)/TAZ in HEK293A cells[3].
[1]. Ohta H, et al. Ki16425, a subtype-selective antagonist for EDG-family lysophosphatidic acid receptors.Mol Pharmacol, 2003, 64(4), 994-1005.
[2]. Moughal NA, et al. Protean agonism of the lysophosphatidic acid receptor-1 with Ki16425 reduces nerve growth factor-induced neurite outgrowth in pheochromocytoma 12 cells. J Neurochem, 2006, 98(6), 1920-1929.
[3]. Yu FX, et al. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell. 2012 Aug 17;150(4):780-91.
[4]. Ma L, et al. Evidence for lysophosphatidic acid 1 receptor signaling in the early phase of neuropathic pain mechanisms in experiments using Ki-16425, a lysophosphatidic acid 1 receptor antagonist. J Neurochem, 2009, 109(2), 603-610.
