Pentamidine (MP-601205) dimesylate is an antimicrobial agent and interferes with DNA biosynthetics. Pentamidine dimesylate inhibits parasite Leishmania infantum with an IC50 of 2.5 μM. Pentamidine dimesylate is a potent and selective protein tyrosine phosphatases (PTPases) and phosphatase of regenerating liver (PRL) inhibitor. Pentamidine dimesylate has the potential for Gambian trypanosomiasis, antimony-resistant leishmaniasis, and Pneumocystis carinii pneumonia treatment. Antitumor and antibacterial activities[1][2][3][4].
体外研究 (In Vitro)
Pentamidine (0-10 µg/mL; 6 days; WM9, DU145, C4-2, Hey, WM480, and A549 cells) dimesylate treatment inhibits the growth of cancer cells in a concentration-dependent manner[1]. The cytotoxic properties of Pentamidine isethionate towards the promastigotes of the protozoan parasite Leishmania infantum is determined. The leishmanicidal activity of Pentamidine isethionate is 60 times higher after 72 h of incubation than that of Cisplatin. Pentamidine isethionate induces a higher amount of programmed cell death (PCD) than Cisplatin, which is associated with inhibition of DNA synthesis and cell-cycle arrest in the G2/M phase. Binding of Pentamidine isethionate to calf-thymus DNA (CT-DNA) induces conformational changes in the DNA double helix, consistent with a B–>A transition. The interaction of Pentamidine isethionate with ubiquitin leads to a 6% increase in the beta-sheet content of the protein[2].
Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.
Cell Viability Assay[1]
Cell Line:
WM9, DU145, C4-2, Hey, WM480, and A549 cells
Concentration:
0-10 µg/mL
Incubation Time:
6 days
Result:
The growth of all six of the cell lines in culture was inhibited in a concentration-dependent manner with complete growth inhibition of the cell lines occurring at 10 µg/mL.
体内研究 (In Vivo)
Pentamidine (0.25 mg/mouse; intramuscular injection; every 2 days; for 4 weeks; athymic nude mice) dimesylate treatment markedly inhibits the growth of WM9 human melanoma tumors in nude mice[1].
Shanghai Jinpan Biotech Co Ltd has not independently confirmed the accuracy of these methods. They are for reference only.
Animal Model:
Athymic nude mice (6 weeks old) injected with WM9 cells[1]
Dosage:
0.25 mg/mouse
Administration:
Intramuscular injection; every 2 days; for 4 weeks
Result:
Markedly inhibited the growth of WM9 human melanoma tumors in nude mice.
分子量
532.63
Formula
C21H32N4O8S2
CAS 号
6823-79-6
中文名称
喷他脒二甲磺酸盐；喷它咪二甲磺酸盐；戊烷脒二甲磺酸盐；戊脘脒二甲磺酸盐
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]. Pathak MK, et al. Pentamidine is an inhibitor of PRL phosphatases with anticancer activity. Mol Cancer Ther. 2002 Dec;1(14):1255-64.
[2]. Nguewa, P.A., et al., Pentamidine is an antiparasitic and apoptotic drug that selectively modifies ubiquitin. Chem Biodivers, 2005. 2(10): p. 1387-400.
[3]. Sands M, et al. Pentamidine: a review. Rev Infect Dis. 1985 Sep-Oct;7(5):625-34.
[4]. David C. Bean, et al. Pentamidine: a drug to consider re-purposing in the targeted treatment of multi-drug resistant bacterial infections? J Lab Precis Med 2017;2:49.
Intoplicine dimesylate(Synonyms: RP 60475 dimesylate) 纯度: 98.28%
Intoplicine (RP 60475) dimesylate，一种 7H 苯并 [e] 吡啶并 [4,3-b] 吲哚系列的抗肿瘤衍生物，是一种 DNA 拓扑异构酶 I 和 II 抑制剂。Intoplicine dimesylate 与 DNA (KA = 2 x 105 /M) 强烈结合，从而增加线性 DNA 的长度。
Intoplicine dimesylate Chemical Structure
CAS No. : 133711-99-6
规格
价格
是否有货
数量
5 mg
￥8000
In-stock
10 mg
￥13000
In-stock
50 mg
询价
100 mg
询价
* Please select Quantity before adding items.
Intoplicine dimesylate 相关产品
•相关化合物库:
Clinical Compound Library Plus
Bioactive Compound Library Plus
生物活性
Intoplicine (RP 60475) dimesylate, an antitumor derivative in the 7H-benzo[e]pyrido[4,3-b]indole series, is a DNA topoisomerase I and II inhibitor. Intoplicine dimesylate strongly binds DNA (KA = 2 x 105 /M) and thereby increases the length of linear DNA[1][2].
IC50 & Target
Topoisomerase I
Topoisomerase II
体外研究 (In Vitro)
With 1-hour exposure to Intoplicine dimesylate at final concentrations of 2.5 micrograms/mL and 10.0 micrograms/mL, 26% and 54% of the assessable specimens shows positive in vitro responses, respectively[2]. With continuous exposure to Intoplicine dimesylate at concentrations of 0.25 micrograms/mL and 2.5 micrograms/mL, 16% and 71% of the assessable specimens showed positive responses, respectively[2]. Activity is seen against breast (71%), non-small-cell lung (69%), and ovarian (45%) cancer colony-forming units at a Intoplicine dimesylate concentration of 10.0 micrograms/mL after 1-hour exposure[2].
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)
At the highest non-toxic dose (HNTD) (6 mg/kg/injection, total dose, 36 mg/kg), intoplicine dimesylate shows highly active with a T/C of 0% and a corresponding total log cell kill of 3[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
540.65
Formula
C23H32N4O7S2
CAS 号
133711-99-6
运输条件
Room temperature in continental US; may vary elsewhere.
储存方式
4°C, sealed storage, away from moisture and light
*In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture and light)
溶解性数据
In Vitro:
DMSO : 115 mg/mL (212.71 mM; Need ultrasonic)
H2O : 100 mg/mL (184.96 mM; Need ultrasonic)
配制储备液
浓度溶剂体积质量
1 mg
5 mg
10 mg
1 mM
1.8496 mL
9.2481 mL
18.4963 mL
5 mM
0.3699 mL
1.8496 mL
3.6993 mL
10 mM
0.1850 mL
0.9248 mL
1.8496 mL
*
请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture and light)。-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。
In Vivo:
请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照 In Vitro 方式配制澄清的储备液，再依次添加助溶剂：
[1]. Riou JF, et al. Intoplicine (RP 60475) and its derivatives, a new class of antitumor agents inhibiting both topoisomerase I and II activities. Cancer Res. 1993;53(24):5987-5993.
[2]. Eckardt JR, et al. Activity of intoplicine (RP60475), a new DNA topoisomerase I and II inhibitor, against human tumor colony-forming units in vitro. J Natl Cancer Inst. 1994;86(1):30-33.
[3]. Bissery MC, et al. Antitumor activity of intoplicine (RP 60475, NSC 645008), a new benzo-pyrido-indole: evaluation against solid tumors and leukemias in mice. Invest New Drugs. 1993;11(4):263-277.
Intoplicine dimesylate(Synonyms: RP 60475 dimesylate) 纯度: 98.28%
Intoplicine (RP 60475) dimesylate，一种 7H 苯并 [e] 吡啶并 [4,3-b] 吲哚系列的抗肿瘤衍生物，是一种 DNA 拓扑异构酶 I 和 II 抑制剂。Intoplicine dimesylate 与 DNA (KA = 2 x 105 /M) 强烈结合，从而增加线性 DNA 的长度。
Intoplicine dimesylate Chemical Structure
CAS No. : 133711-99-6
规格
价格
是否有货
数量
5 mg
￥8000
In-stock
10 mg
￥13000
In-stock
50 mg
询价
100 mg
询价
* Please select Quantity before adding items.
Intoplicine dimesylate 相关产品
•相关化合物库:
Clinical Compound Library Plus
Bioactive Compound Library Plus
生物活性
Intoplicine (RP 60475) dimesylate, an antitumor derivative in the 7H-benzo[e]pyrido[4,3-b]indole series, is a DNA topoisomerase I and II inhibitor. Intoplicine dimesylate strongly binds DNA (KA = 2 x 105 /M) and thereby increases the length of linear DNA[1][2].
IC50 & Target
Topoisomerase I
Topoisomerase II
体外研究 (In Vitro)
With 1-hour exposure to Intoplicine dimesylate at final concentrations of 2.5 micrograms/mL and 10.0 micrograms/mL, 26% and 54% of the assessable specimens shows positive in vitro responses, respectively[2]. With continuous exposure to Intoplicine dimesylate at concentrations of 0.25 micrograms/mL and 2.5 micrograms/mL, 16% and 71% of the assessable specimens showed positive responses, respectively[2]. Activity is seen against breast (71%), non-small-cell lung (69%), and ovarian (45%) cancer colony-forming units at a Intoplicine dimesylate concentration of 10.0 micrograms/mL after 1-hour exposure[2].
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)
At the highest non-toxic dose (HNTD) (6 mg/kg/injection, total dose, 36 mg/kg), intoplicine dimesylate shows highly active with a T/C of 0% and a corresponding total log cell kill of 3[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
540.65
Formula
C23H32N4O7S2
CAS 号
133711-99-6
运输条件
Room temperature in continental US; may vary elsewhere.
储存方式
4°C, sealed storage, away from moisture and light
*In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture and light)
溶解性数据
In Vitro:
DMSO : 115 mg/mL (212.71 mM; Need ultrasonic)
H2O : 100 mg/mL (184.96 mM; Need ultrasonic)
配制储备液
浓度溶剂体积质量
1 mg
5 mg
10 mg
1 mM
1.8496 mL
9.2481 mL
18.4963 mL
5 mM
0.3699 mL
1.8496 mL
3.6993 mL
10 mM
0.1850 mL
0.9248 mL
1.8496 mL
*
请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture and light)。-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。
In Vivo:
请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照 In Vitro 方式配制澄清的储备液，再依次添加助溶剂：
[1]. Riou JF, et al. Intoplicine (RP 60475) and its derivatives, a new class of antitumor agents inhibiting both topoisomerase I and II activities. Cancer Res. 1993;53(24):5987-5993.
[2]. Eckardt JR, et al. Activity of intoplicine (RP60475), a new DNA topoisomerase I and II inhibitor, against human tumor colony-forming units in vitro. J Natl Cancer Inst. 1994;86(1):30-33.
[3]. Bissery MC, et al. Antitumor activity of intoplicine (RP 60475, NSC 645008), a new benzo-pyrido-indole: evaluation against solid tumors and leukemias in mice. Invest New Drugs. 1993;11(4):263-277.
Intoplicine dimesylate(Synonyms: RP 60475 dimesylate) 纯度: 98.28%
Intoplicine (RP 60475) dimesylate，一种 7H 苯并 [e] 吡啶并 [4,3-b] 吲哚系列的抗肿瘤衍生物，是一种 DNA 拓扑异构酶 I 和 II 抑制剂。Intoplicine dimesylate 与 DNA (KA = 2 x 105 /M) 强烈结合，从而增加线性 DNA 的长度。
Intoplicine dimesylate Chemical Structure
CAS No. : 133711-99-6
规格
价格
是否有货
数量
5 mg
￥8000
In-stock
10 mg
￥13000
In-stock
50 mg
询价
100 mg
询价
* Please select Quantity before adding items.
Intoplicine dimesylate 相关产品
•相关化合物库:
Clinical Compound Library Plus
Bioactive Compound Library Plus
生物活性
Intoplicine (RP 60475) dimesylate, an antitumor derivative in the 7H-benzo[e]pyrido[4,3-b]indole series, is a DNA topoisomerase I and II inhibitor. Intoplicine dimesylate strongly binds DNA (KA = 2 x 105 /M) and thereby increases the length of linear DNA[1][2].
IC50 & Target
Topoisomerase I
Topoisomerase II
体外研究 (In Vitro)
With 1-hour exposure to Intoplicine dimesylate at final concentrations of 2.5 micrograms/mL and 10.0 micrograms/mL, 26% and 54% of the assessable specimens shows positive in vitro responses, respectively[2]. With continuous exposure to Intoplicine dimesylate at concentrations of 0.25 micrograms/mL and 2.5 micrograms/mL, 16% and 71% of the assessable specimens showed positive responses, respectively[2]. Activity is seen against breast (71%), non-small-cell lung (69%), and ovarian (45%) cancer colony-forming units at a Intoplicine dimesylate concentration of 10.0 micrograms/mL after 1-hour exposure[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)
At the highest non-toxic dose (HNTD) (6 mg/kg/injection, total dose, 36 mg/kg), intoplicine dimesylate shows highly active with a T/C of 0% and a corresponding total log cell kill of 3[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
540.65
Formula
C23H32N4O7S2
CAS 号
133711-99-6
运输条件
Room temperature in continental US; may vary elsewhere.
储存方式
4°C, sealed storage, away from moisture and light
*In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture and light)
溶解性数据
In Vitro:
DMSO : 115 mg/mL (212.71 mM; Need ultrasonic)
H2O : 100 mg/mL (184.96 mM; Need ultrasonic)
配制储备液
浓度溶剂体积质量
1 mg
5 mg
10 mg
1 mM
1.8496 mL
9.2481 mL
18.4963 mL
5 mM
0.3699 mL
1.8496 mL
3.6993 mL
10 mM
0.1850 mL
0.9248 mL
1.8496 mL
*
请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture and light)。-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。
In Vivo:
请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照 In Vitro 方式配制澄清的储备液，再依次添加助溶剂：
[1]. Riou JF, et al. Intoplicine (RP 60475) and its derivatives, a new class of antitumor agents inhibiting both topoisomerase I and II activities. Cancer Res. 1993;53(24):5987-5993.
[2]. Eckardt JR, et al. Activity of intoplicine (RP60475), a new DNA topoisomerase I and II inhibitor, against human tumor colony-forming units in vitro. J Natl Cancer Inst. 1994;86(1):30-33.
[3]. Bissery MC, et al. Antitumor activity of intoplicine (RP 60475, NSC 645008), a new benzo-pyrido-indole: evaluation against solid tumors and leukemias in mice. Invest New Drugs. 1993;11(4):263-277.
Ralimetinib dimesylate (LY2228820 dimesylate) is a selective, ATP-competitive inhibitor of p38 MAPK α/β with IC50s of 5.3 and 3.2 nM, respectively. Ralimetinib (LY2228820) selectively inhibits phosphorylation of MK2 (Thr334), with no effect on phosphorylation of p38a MAPK, JNK, ERK1/2, c-Jun, ATF2, or c-Myc.
IC50 & Target[3]
p38β MAPK
3.2 nM (IC50)
p38α MAPK
5.3 nM (IC50)
体外研究 (In Vitro)
Ralimetinib dimesylate inhibits p38α, as well as the level of phosphoMAPKAPK-2 (pMK2) in RAW 264.7 cells, with IC50 values of 7 nM and 34.3 nM, respectively. Furthermore, Ralimetinib dimesylate inhibits lipopolysaccharide (LPS)-induced TNFα formation in murine peritoneal macrophages, with IC50 of 5.2 nM[1]. In multiple myeloma (MM) cells, including INA6, RPMI-8226, U266, and RPMI-Dox40, Ralimetinib dimesylate (LY2228820) (200 nM-800 nM) significantly blocks p38MAPK signaling, as revealed by its inhibition on phosphorylation of HSP27, a downstream target of p38MAPK, without affecting the expression level of HSP27. Ralimetinib dimesylate (200 nM-400 nM) enhances bortezomib-induced cytotoxicity and apoptosis, but Ralimetinib dimesylate alone doesn’t inhibit the growth of MM.1S cells. Ralimetinib dimesylate (200 nM-800 nM) also inhibits secretion of IL-6 and MIP-1α in long-term BM stromal cells (LT-BMSCs), BM mononuclear cells (BMMNCs), peripheral blood (PB) CD138+, CD138– or PB CD14+ cells. Ralimetinib dimesylate (400 nM-800 nM) also blocks osteoclastogenesis from CD14+ cells[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)
In LPS-induced mice, Ralimetinib dimesylate effectively inhibits the formation of TNFα with a threshold minimum 50% effective dose (TMED50) less than 1 mg/kg. In a rat model of collagen-inducedarthritis (CIA), Ralimetinib dimesylate displays potent effects on paw swelling, bone erosion, and cartilage destruction, with a threshold minimum 50% effective dose (TMED50)of 1.5 mg/kg[1]. Ralimetinib dimesylate inhibits tumor phospho-MK2 in a dose-dependent manner (TED50=1.95 mg/kg, TED70=11.17 mg/kg) in mice implanted with B16-F10 melanoma. Ralimetinib dimesylate inhibits MK2 phosphorylation: mouse in vivo TED50=1.01 mg/kg (compound exposure approximately 100 nM) and human ex vivo IC50=0.12 μM with either mouse or human PBMC[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
612.74
Formula
C26H37FN6O6S2
CAS 号
862507-23-1
运输条件
Room temperature in continental US; may vary elsewhere.
[1]. Mader M, et al. Imidazolyl benzimidazoles and imidazo[4,5-b]pyridines as potent p38alpha MAP kinase inhibitors with excellent in vivo antiinflammatory properties. Bioorg Med Chem Lett, 2008, 18(1), 179-183.
[2]. Ishitsuka K, et al. p38 mitogen-activated protein kinase inhibitor LY2228820 enhances bortezomib-induced cytotoxicity and inhibits osteoclastogenesis in multiple myeloma; therapeutic implications. Br J Haematol, 2008, 141(5), 598-606.
[3]. Campbell RM, et al. Characterization of LY2228820 dimesylate, a potent and selective inhibitor of p38 MAPK with antitumor activity. Mol Cancer Ther. 2014 Feb;13(2):364-74.
Kinase Assay [1]
Inhibition of p38α is determined using recombinant human p38α in a standard filter binding protocol using ATP[γ-33P] and EGFR 21-mer peptide as substrate. Functional inhibition of TNFα in murine peritoneal macrophages is determined using LPS stimulation in the presence of Ralimetinib. To assess p38α activity in cells more directly, RAW 264.7 cells are treated with Ralimetinib and then stimulated with anisomycin. The level of p38α activity is detected using a phosphoMAPKAPK-2 (pMK2) (Thr 334) antibody which reacts with a residue specifically phosphorylated by p38α.
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 [3]
Murine B16-F10 melanoma cells are cultured in Dulbecco’s Modified Eagle Medium supplemented with l-glutamine, high glucose and 10% FBS (GIBCO 11965-092). C57/bl6 mice are implanted in the rear flank with B16-F10 cells (2×106), and when tumors reach approximately 200 mm3 in size, are dosed orally with Ralimetinib dimesylate in 1% carboxymethylcellulose/0.25% Tween 80. Two hours postdose, tumors are excised, homogenized, and lysed for Western blot analysis. MK2 phosphorylation (p-Thr334), normalized to total glyceraldehyde-3-phosphate dehydrogenase, is quantified by chemiluminescent detection. The 50% or 70% threshold effective dose (TED50 and TED70, respectively) is calculated to approximate effective dose ranges for testing of Ralimetinib dimesylate in xenograft models, that is, where significant target inhibition is observed. The TED50 or TED70 is defined as the dose where a statistically significant effect is achieved, and there is at least 50% or 70% inhibition, respectively, compared with vehicle control.
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]. Mader M, et al. Imidazolyl benzimidazoles and imidazo[4,5-b]pyridines as potent p38alpha MAP kinase inhibitors with excellent in vivo antiinflammatory properties. Bioorg Med Chem Lett, 2008, 18(1), 179-183.
[2]. Ishitsuka K, et al. p38 mitogen-activated protein kinase inhibitor LY2228820 enhances bortezomib-induced cytotoxicity and inhibits osteoclastogenesis in multiple myeloma; therapeutic implications. Br J Haematol, 2008, 141(5), 598-606.
[3]. Campbell RM, et al. Characterization of LY2228820 dimesylate, a potent and selective inhibitor of p38 MAPK with antitumor activity. Mol Cancer Ther. 2014 Feb;13(2):364-74.
Osimertinib dimesylate (AZD-9291 dimesylate) is an irreversible and mutant selective EGFR inhibitor with IC50s of 12 and 1 nM against EGFRL858R and EGFRL858R/T790M, respectively.
IC50 & Target[1]
EGFRL858R
12 nM (IC50)
EGFRL858R/T790M
1 nM (IC50)
体外研究 (In Vitro)
Osimertinib (AZD-9291) shows similar potency to early generation tyrosine kinase inhibitor (TKIs) in inhibiting EGFR phosphorylation in EGFR cells harboring sensitising EGFR mutants including PC-9 (ex19del), H3255 (L858R) and H1650 (ex19del), with mean IC50 values ranging from 13 to 54 nM for Osimertinib (AZD-9291). Osimertinib (AZD-9291) also potently inhibits phosphorylation of EGFR in T790M mutant cell lines (H1975 (L858R/T790M), PC-9VanR (ex19del/T790M), with mean IC50 potency less than 15 nM[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 tumor-bearing mice are treated with Osimertinib (AZD-9291) (5 mg/kg/day) for one to two weeks. Within days of treatment, 5 of 5 C/L858R mice displays nearly 80% reduction in tumor volume by magnetic resonance imaging MRI after therapy with Osimertinib (AZD-9291), while 5 of 5 mice treated with vehicle shows tumor growth[1]. Osimertinib (AZD-9291) demonstrates improved rat PK, reduced hERG affinity, and improved IGF1R margins relative to the previously described compounds, and so this compound is selected for further investigation. Osimertinib (AZD-9291) also offers an additional degree of broader chemical and profile diversity when compared to the previously described lead compounds. Upon dosing Osimertinib (AZD-9291) in three efficacy models, The comparable efficacy is observed at relatively low doses (10 mg/kg per day). The excellent efficacy is also observed when Osimertinib (AZD-9291) is dosed at 5 mg/kg per day[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
691.82
Formula
C30H41N7O8S2
CAS 号
2070014-82-1
中文名称
奥斯替尼二甲磺酸盐；奥希替尼二甲磺酸盐
运输条件
Room temperature in continental US; may vary elsewhere.
[1]. Cross DA, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014 Sep;4(9):1046-61.
[2]. Finlay MR, et al. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistancemutations that spares the wild type form of the receptor. J Med Chem. 2014 Oct 23;57(20):8249-67.
Cell Assay [1]
PC-9 cells are seeded into T75 flasks (5×105 cells/flask) in RPMI growth media and incubated at 37°C, 5% CO2. The following day the media is replaced with media supplemented with a concentration of EGFR inhibitor equal to the EC50 concentration predetermined in PC-9 cells. Media changes are carried out every 2-3 days and resistant clones allowed to grow to 80% confluency prior to the cells being trypsinised and reseeded at the original seeding density in media containing twice the concentration of EGFR inhibitor. Dose escalations are continued until a final concentration of 1.5 μM ZD1839, 1.5 μM BIBW 2992, 1.5 μM WZ4002 or 160 nM Osimertinib (AZD-9291) are achieved[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]
Mice[1] The EGFRL858R and EGFRL858R+T790M mice (male and female) are used. Osimertinib (AZD-9291) is suspended in 1% Polysorbate 80 and administered via oral gavage once daily at the doses of 7.5 mg/kg and 5 mg/kg, respectively. Mice are imaged weekly at the Vanderbilt University Institute of Imaging Science. For immunoblot analysis, mice are treated for eight hours with drug as described before dissection and flash freezing of the lungs. Lungs are pulverized in liquid nitrogen before lysis. Rats[2] The male RccHan:WIST rats (10-week-old) are received a single oral dose of Osimertinib (AZD-9291) (200 mg/kg). Blood glucose levels are measured using an Accuchek Active meter.
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]. Cross DA, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014 Sep;4(9):1046-61.
[2]. Finlay MR, et al. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistancemutations that spares the wild type form of the receptor. J Med Chem. 2014 Oct 23;57(20):8249-67.
Prexasertib dimesylate (LY2606368 dimesylate) is a selective, ATP-competitive second-generation checkpoint kinase 1 (CHK1) inhibitor with a Ki of 0.9 nM and an IC50 of <1 nm. prexasertib dimesylate inhibits chk2 (ic50=8 nM) and RSK1 (IC50=9 nM). Prexasertib dimesylate causes double-stranded DNA breakage and replication catastrophe resulting in apoptosis. Prexasertib dimesylate shows potent anti-tumor activity[1][2].
IC50 & Target[1]
Chk1
0.9 nM (Ki)
Chk1
<1 nM (IC50)
Chk2
8 nM (IC50)
体外研究 (In Vitro)
Prexasertib dimesylate (LY2606368 dimesylate) inhibits MELK (IC50=38 nM), SIK (IC50=42 nM), BRSK2 (IC50=48 nM), ARK5 (IC50=64 nM). Prexasertib dimesylate requires CDC25A and CDK2 to cause DNA damage[1]. Prexasertib dimesylate (33, 100 nM; for 7 hours) results in DNA damage during S-phase in HeLa cells[1]. Prexasertib dimesylate (8-250 nM; pre-treated for 15 minutes) inhibits CHK1 autophosphorylation (S296) and CHK2 autophosphorylation (S516) in HT-29 cells[1]. Prexasertib dimesylate (4 nM; 24 hours) results in a large shift in cell-cycle populations from G1 and G2-M to S-phase with an accompanied induction of H2AX phosphorylation in U-2 OS cells[1]. Prexasertib dimesylate (33 nM; for 12 hours) causes chromosomal fragmentation in HeLa cells. Prexasertib dimesylate (100 nM; 0.5 to 9 hours) induces replication stress and depletes the pool of available RPA2 for binding to DNA[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 Cycle Analysis[1]
Cell Line:
HeLa cells
Concentration:
33, 100 nM
Incubation Time:
For 7 hours
Result:
Had an IC50 of 37 nM and resulted in the G2-M population received DNA damage during S-phase but continued to progress through the cell cycle into an early mitosis.
Western Blot Analysis[1]
Cell Line:
HT-29 cells
Concentration:
8, 16, 31, 63, 125, 250 nM
Incubation Time:
Pre-treated for 15 minutes
Result:
Inhibited CHK1 autophosphorylation (S296) and CHK2 autophosphorylation (S516) (IC50 of less than 31 nM) in HT-29 cells.
体内研究 (In Vivo)
Prexasertib dimesylate (LY2606368 dimesylate; 1-10 mg/kg; SC; twice daily for 3 days, rest 4 days; for three cycles) causes growth inhibition in tumor xenografts[1]. Prexasertib dimesylate (15 mg/kg; SC) causes CHK1 inhibition in the blood and the phosphorylation of both H2AX (S139) and RPA2 (S4/S8)[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:
Female CD-1 nu-/nu- mice (26-28 g) with Calu-6 cells[1]
Dosage:
1, 3.3, or 10 mg/kg
Administration:
SC; twice daily for 3 days, rest 4 days; for three cycles
Result:
Caused statistically significant tumor growth inhibition (up to 72.3%).
Animal Model:
Female CD-1 nu-/nu- mice (26-28 g) with Calu-6 cells[1]
Dosage:
15 mg/kg (Pharmacokinetic Analysis)
Administration:
SC (200 μL)
Result:
CHK1 was 7 ng/mL at 12 hours and 3 ng/mL by 24 hours in plasma exposures. Phosphorylation of both H2AX (S139) and RPA2 (S4/S8) was detectable at 4 hours, showing the rapid occurrence of DNA damage.
Clinical Trial
分子量
557.60
Formula
C20H27N7O8S2
CAS 号
1234015-58-7
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]. King C, et al. LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms. Mol Cancer Ther. 2015 Sep;14(9):2004-1
[2]. Yin Y, et al. Chk1 inhibition potentiates the therapeutic efficacy of PARP inhibitor BMN673 in gastric cancer. Am J Cancer Res. 2017 Mar 1;7(3):473-483.
Olverembatinib (GZD824) dimesylate is a potent and orally active pan-Bcr-Abl inhibitor. Olverembatinib dimesylate potently inhibits a broad spectrum of Bcr-Abl mutants. Olverembatinib dimesylate strongly inhibits native Bcr-Abl and Bcr-AblT315I with IC50s of 0.34 nM and 0.68 nM, respectively. Olverembatinib dimesylate has antitumor activity[1].
[1]. Ren X, Pan X, Zhang Z, Identification of GZD824 as an orally bioavailable inhibitor that targets phosphorylated and nonphosphorylated breakpoint cluster region-Abelson (Bcr-Abl) kinase and overcomes clinically acquired mutation-induced resistance against imatinib. J Med Chem. 2013 Feb 14;56(3):879-94.
