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Identification of Type II Inhibitors Targeting BRAF Using Privileged Pharmacophores
Author(s) -
Zhang Qingwen,
Wang Juan,
Wang Fei,
Chen Xiuhua,
He Yunsong,
You Qidong,
Zhou Houyuan
Publication year - 2014
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12198
Subject(s) - pharmacophore , kinase , chemistry , docking (animal) , cancer research , oncogene , mapk/erk pathway , computational biology , biology , biochemistry , medicine , apoptosis , cell cycle , nursing
V‐RAF murine sarcoma viral oncogene homologue B1 ( BRAF ) is the most frequently mutated protein kinase in human cancers. The most common mutant BRAF V600E constitutively activates the RAS / RAF / MEK / ERK signaling pathway. BRAF has been validated as an important therapeutic target in human cancers. Phenylaminopyrimidine and unsymmetrical diaryl urea are two privileged pharmacophores in kinase inhibitor drug discovery. Herein, we describe the design of a novel hybrid pharmacophore, 4‐phenylaminopyrimidine urea, using the above two pharmacophores. A new series of compounds were in turn synthesized and evaluated to successfully identify selective inhibitors of BRAF and oncogenic BRAF V600E. Once daily oral dosing of lead compound 3 demonstrated sustained antitumor efficacy in A549 human non‐small‐cell lung cancer xenograft model. Molecular docking suggested that compound 3 might be a type II kinase inhibitor binding to the DFG ‐out conformation of BRAF .