2. Academic Validation
  3. Structure-guided discovery of a novel, potent, and orally bioavailable 3,5-dimethylisoxazole aryl-benzimidazole BET bromodomain inhibitor

Structure-guided discovery of a novel, potent, and orally bioavailable 3,5-dimethylisoxazole aryl-benzimidazole BET bromodomain inhibitor

  • Bioorg Med Chem. 2019 Feb 1;27(3):457-469. doi: 10.1016/j.bmc.2018.11.020.
David Sperandio 1,  Vangelis Aktoudianakis 2,  Kerim Babaoglu 3,  Xiaowu Chen 3,  Kristyna Elbel 2,  Gregory Chin 2,  Britton Corkey 2,  Jinfa Du 2,  Bob Jiang 2,  Tetsuya Kobayashi 2,  Richard Mackman 2,  Ruben Martinez 2,  Hai Yang 2,  Jeff Zablocki 2,  Saritha Kusam 4,  Kim Jordan 4,  Heather Webb 4,  Jamie G Bates 4,  Latesh Lad 4,  Michael Mish 2,  Anita Niedziela-Majka 4,  Sammy Metobo 2,  Annapurna Sapre 4,  Magdeleine Hung 4,  Debi Jin 4,  Wanchi Fung 4,  Elaine Kan 4,  Gene Eisenberg 5,  Nate Larson 4,  Zachary E R Newby 3,  Eric Lansdon 3,  Chin Tay 4,  Richard M Neve 4,  Sophia L Shevick 2,  David G Breckenridge 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. Electronic address: [email protected].
  • 2 Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
  • 3 Department of Structural Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
  • 4 Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
  • 5 Department of Drug Metabolism, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
PMID: 30606676 DOI: 10.1016/j.bmc.2018.11.020
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.

Keywords

Antitumor; BET proteins; Bromodomain inhibitor; Epigenetic readers.

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