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

David Sperandio; Vangelis Aktoudianakis; Kerim Babaoglu; Xiaowu Chen; Kristyna Elbel; Gregory Chin; Britton Corkey; Jinfa Du; Bob Jiang; Tetsuya Kobayashi; Richard Mackman; Ruben Martinez; Hai Yang; Jeff Zablocki; Saritha Kusam; Kim Jordan; Heather Webb; Jamie G Bates; Latesh Lad; Michael Mish; Anita Niedziela-Majka; Sammy Metobo; Annapurna Sapre; Magdeleine Hung; Debi Jin; Wanchi Fung; Elaine Kan; Gene Eisenberg; Nate Larson; Zachary E R Newby; Eric Lansdon; Chin Tay; Richard M Neve; Sophia L Shevick; David G Breckenridge

doi:10.1016/j.bmc.2018.11.020

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. Epub 2018 Nov 15.

Authors

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

Affiliations

¹ Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. Electronic address: david.sperandio@r2mpharma.com.
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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Administration, Oral
Animals
Benzimidazoles / chemistry
Benzimidazoles / metabolism
Benzimidazoles / pharmacology*
Biological Availability
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Isoxazoles / administration & dosage
Isoxazoles / chemistry
Isoxazoles / metabolism
Isoxazoles / pharmacology*
Mice
Molecular Structure
Multiple Myeloma / drug therapy*
Multiple Myeloma / metabolism
Multiple Myeloma / pathology
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Protein Domains / drug effects
Structure-Activity Relationship
Transcription Factors / antagonists & inhibitors*
Transcription Factors / metabolism

Substances

Benzimidazoles
Isoxazoles
Transcription Factors

Grants and funding

S10 OD021832/OD/NIH HHS/United States