BI-882370 是高选择性的Raf激酶抑制剂，其结合位于 BRaf 激酶的 DFG-out 无活性构象处 (ATP 结合位点)。 它抑制 Src 家族激酶，也抑制 BRafV600E-mutant、WT BRaf 和 CRaf 激酶，IC50值分别为 0.4、0.8 和 0.6 nM。

BI-882370 is a specific RAF kinase inhibitor. BI-882370 inhibits the oncogenic BRAFV600E-mutant, the WT BRAF and CRAF kinases (IC50s: 0.4, 0.8 and 0.6 nM). BI-882370 also inhibits SRC family kinases.

BI-882370 (0.9-6000 nM; 3 days) inhibits the BRAF-mutant human melanoma and colorectal cancer cell proliferation (EC50: 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.

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 show superior efficacy compared with Vemurafenib, Dabrafenib, or Trametinib. BI-882370 (p.o; 25 mg/kg; twice daily; 40 days) develops 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) show a lack of toxicity in terms of clinical chemistry, hematology, pathology, and toxicogenomics in rats.

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

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

1392429-79-6

C28H33F2N7O2S

569.67

DMSO:5 mg/mL (8.78 mM),ultrasonic and warming and heat to 60°C
Powder: -20°C for 3 years
In solvent: -80°C for 2 years