Lead Discovery of Type II BRAF V600E Inhibitors Targeting the Structurally Validated DFG-Out Conformation Based upon Selected Fragments.

ABSTRACT: The success of the first approved kinase inhibitor imatinib has spurred great interest in the development of type II inhibitors targeting the inactive DFG-out conformation, wherein the Phe of the DFG motif at the start of the activation loop points into the ATP binding site. Nevertheless, kinase inhibitors launched so far are heavily biased toward type I inhibitors targeting the active DFG-in conformation, wherein the Phe of the DFG motif flips by approximately 180° relative to the inactive conformation, resulting in Phe and Asp swapping their positions. Data recently obtained with structurally validated type II inhibitors supported the conclusion that type II inhibitors are more selective than type I inhibitors. In our type II BRAF V600E inhibitor lead discovery effort, we identified phen

SUBMITTER: Zhang Q 

PROVIDER: S-EPMC6272942 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature