BI 882370

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

BI 882370 是一种高效、选择性、口服活性的 RAF 抑制剂，对 BRAF V600E、BRAF WT 和 CRAF 的 IC50 分别为 0.4、0.8 和 0.6 nM。

BI 882370 is a highly potent, selective, orally active RAF inhibitor with IC50 of 0.4, 0.8 and 0.6 nM for BRAF V600E, BRAF WT and CRAF, respectively; demonstrates excellent selectivity (>100-fold) against a panel of 253 kinases (The most sensitive kinase CSF1R IC50=39 nM); binds to the DFG-out (inactive) conformation of the BRAF kinase, unlike vemurafenib and dabrafenib; reduces p-MEK1/2 and p-ERK1/2 signals in BRAFV600E mutation A375 cells (EC50=0.3 nM), inhibits cell proliferation of a panel BRAF-mutant human melanoma and colorectal cancer cell lines (EC50=1-10 nM); demonstrates in vivo anti-cancer activity against human melanoma xenografts in nude mice.

BI-882370 (0.9-6000 nM; 3 days) inhibits the BRAF-mutant human melanoma and colorectal cancer cells proliferation with a EC50 range of 1-10 nM.BI 882370 (0.1-100 nM, 0.1-3000 nM; 2 hours) results in a reduction of p-MEK1/2, p-ERK1/2 and cyclin D1/D2 expression in BRAFV600E-mutant A375 cells; induces phosphorylation of MEK1/2 and enhanced phosphorylation of ERK1/2 in WT BRO cells (3-300 nM).BI 882370 (0.1-100 nM, 0.1-3000 nM; 24 hours) suppresses cyclin D1/D2 expression, induces Kip1/p27 expression at concentrations of 1 nM or higher in BRAFV600E-mutant A375 cells, expression of cyclins D1/D2 or Kip1/p27 is not affected in WT BRO cells. Cell Proliferation Assay Cell Line:BRAF-mutant and WT melanoma cell lines (A101D, A375, SK-MEL-28, G-361, and BRO); Colorectal cancer cell lines (COLO 205, HT-29, LS411N, and HCT-116)Concentration: 0.9-6000 nM Incubation Time:3 days Result:Showed a EC50 range of 1-10 nM in an extended panel of BRAF-mutant human melanoma and colorectal cancer cell; while proliferation of BRAF WT cells was inhibited with EC50 >1 μM.Western Blot Analysis Cell Line:BRAFV600E-mutant A375 cells; BRAF WT, NRAS-mutant BRO (WT BRO) cells Concentration:0.1-100 nM; 0.1-3000 nM Incubation Time:2 hours; 24 hours Result:Resulted in a reduction of phospho-MEK1/2 signals and cyclin D1/D2 expression in BRAFV600E-mutant A375 cells.

BI-882370 (deliver orally; 25 mg/kg, 50 mg/kg; twice daily; 2 weeks) is efficacious in multiple mouse models of BRAF-mutant melanomas and colorectal carcinomas, shows superior efficacy compared with Vemurafenib, Dabrafenib, or Trametinib.BI-882370 (deliver orally; 25 mg/kg; twice daily; 40 days) developes resistance within 3 weeks,but resistance is not observed during 5 weeks of second-line therapy in combination with trametinib. BI-882370 (deliver orally; 60 mg/kg; once daily; 2 weeks) indicates lack of toxicity in terms of clinical chemistry, hematology, pathology, and toxicogenomics in rats. Animal Model:Human melanoma xenografts in nude mice with BRAF-mutant melanomas and colorectal carcinomas cells (A375, COLO 205; G-361, HT-29 cells)Dosage:25 mg/kg; 50 mg/kg Administration:Deliver orally; 25 mg/kg, 50 mg/kg; twice daily; 2 weeks Result:Regressed tumors partially, upon discontinuation, tumor regrowth was markedly delayed.

BI882370

MAPK/ERK Signaling

Raf

Raf

——

——

1392429-79-6

569.676

C28H33F2N7O2S

>98% (HPLC)

In Vitro:?DMSO : 5 mg/mL (8.78 mM)

CCN1CCC(N(C)C2=CC=C(N(C3=C(F)C=CC(NS(CCC)(=O)=O)=C3F)C=C4C5=CN=CN=C5)C4=N2)CC1

Propane-1-sulfonic acid (3-{5-[(1-ethyl-piperidin-4-yl)-methyl-amino]-3-pyrimidin-5-yl-pyrrolo[3,2-b]pyridin-1-yl}-2,4-difluoro-phenyl)-amide

(-20℃)

With Ice Pack

≥ 2 years