BI 882370| CAS 1392429-79-6

Cas No.:	1392429-79-6
Chemical Name:	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
Synonyms:	BI882370,BI-882370
SMILES:	CCCS(=O)(NC1=CC=C(F)C(N2C=C(C3=CN=CN=C3)C4=NC(N(C5CCN(CC)CC5)C)=CC=C42)=C1F)=O
Formula:	C₂₈H₃₃F₂N₇O₂S
M.Wt:	569.676
Purity:	>98%
Sotrage:	2 years -20°C Powder, 2 weeks4°C in DMSO,6 months-80°C in DMSO

Description:	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 BRAFV600E-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].
Target:	Braf:0.6 nM (IC50) c-Raf:0.8 nM (IC50) BRafV600E:0.4 nM (IC50)
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]. Animal Model: Human melanoma xenografts in nude mice with BRAF-mutant melanomas and colorectal carcinomas cells (A375, COLO 205; G-361, HT-29 cells)[1] 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.
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, 24 hours) results in a reduction of p-MEK1/2, p-ERK1/2 and cyclin D1/D2 expression in BRAFV600E-mutant A375 cells; induces p-MEK1/2 and enhances p-ERK1/2 , cyclins D1/D2 or Kip1/p27 is not affected in BRO cells[1]. Cell Proliferation Assay[1] 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 >1μM. Western Blot Analysis[1] 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.
References:	[1]. Waizenegger IC, et al. A Novel RAF Kinase Inhibitor with DFG-Out-Binding Mode: High Efficacy in BRAF-Mutant Tumor Xenograft Models in the Absence of Normal Tissue Hyperproliferation. Mol Cancer Ther. 2016 Mar;15(3):354-65.

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