| Literature DB >> 30606676 |
David Sperandio1, Vangelis Aktoudianakis2, Kerim Babaoglu3, Xiaowu Chen3, Kristyna Elbel2, Gregory Chin2, Britton Corkey2, Jinfa Du2, Bob Jiang2, Tetsuya Kobayashi2, Richard Mackman2, Ruben Martinez2, Hai Yang2, Jeff Zablocki2, Saritha Kusam4, Kim Jordan4, Heather Webb4, Jamie G Bates4, Latesh Lad4, Michael Mish2, Anita Niedziela-Majka4, Sammy Metobo2, Annapurna Sapre4, Magdeleine Hung4, Debi Jin4, Wanchi Fung4, Elaine Kan4, Gene Eisenberg5, Nate Larson4, Zachary E R Newby3, Eric Lansdon3, Chin Tay4, Richard M Neve4, Sophia L Shevick2, David G Breckenridge4.
Abstract
The bromodomain and extra-terminal (BET) family of proteins, consisting of the bromodomains containing protein 2 (BRD2), BRD3, BRD4, and the testis-specific BRDT, are key epigenetic regulators of gene transcription and has emerged as an attractive target for anticancer therapy. Herein, we describe the discovery of a novel potent BET bromodomain inhibitor, using a systematic structure-based approach focused on improving potency, metabolic stability, and permeability. The optimized dimethylisoxazole aryl-benzimidazole inhibitor exhibited high potency towards BRD4 and related BET proteins in biochemical and cell-based assays and inhibited tumor growth in two proof-of-concept preclinical animal models.Entities:
Keywords: Antitumor; BET proteins; Bromodomain inhibitor; Epigenetic readers
Year: 2018 PMID： 30606676 DOI： 10.1016/j.bmc.2018.11.020
Source DB: PubMed Journal: Bioorg Med Chem ISSN： 0968-0896 Impact factor: 3.641