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 IC₅₀s of 0.4, 0.8, and 0.6 nM, respectively. BI-882370 also inhibits SRC family kinases^[1]. IC50 & Target: IC50: of 0.4 nM (BRAF^V600E-mutant kinase), 0.8 nM (WT BRAF kinase), 0.6 nM (CRAF kinase)^[1] In Vitro: 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^[1].
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)^[1].
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^[1].
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^[1].
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^[1].
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^[1].