BI-882370

BI-882370 is a potent and selective RAF kinase inhibitor that binds to the ATP binding site of the kinase positioned in the DFG-out (inactive) conformation of the BRAF kinase. BI-882370 (BI 882370) inhibits the oncogenic BRAF V600E -mutant, the WT BRAF and CRAF kinases with IC 50 s of 0.4, 0.8, and 0.6 nM, respectively. BI-882370 also inhibits SRC family kinases In Vitro BI-882370 (0.9-6000 nM; 3 days) inhibits the BRAF-mutant human melanoma and colorectal cancer cells proliferation with a EC 50 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 BRAF V600E -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 BRAF V600E -mutant A375 cells, expression of cyclins D1/D2 or Kip1/p27 is not affected in WT BRO cells. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Proliferation AssayCell 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 EC 50 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 EC 50 >1 μM. Western Blot AnalysisCell Line: BRAF V600E -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 BRAF V600E -mutant A375 cells. In Vivo 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 . MCE has not independently confirmed the accuracy of these methods. They are for reference only. 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. Form:Solid IC50& Target:Braf 0.6 nM (IC 50 ) c-Raf 0.8 nM (IC 50 ) BRaf V600E 0.4 nM (IC 50 )

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