Design, synthesis and biological evaluation of imidazo[1,5-a]pyrazin-8(7H)-one derivatives as BRD9 inhibitors

Peiyuan Zheng; Jian Zhang; Hui Ma; Xinrui Yuan; Pan Chen; Jinpei Zhou; Huibin Zhang

doi:10.1016/j.bmc.2019.02.045

Design, synthesis and biological evaluation of imidazo[1,5-a]pyrazin-8(7H)-one derivatives as BRD9 inhibitors

Bioorg Med Chem. 2019 Apr 1;27(7):1391-1404. doi: 10.1016/j.bmc.2019.02.045. Epub 2019 Feb 21.

Authors

Peiyuan Zheng¹, Jian Zhang¹, Hui Ma¹, Xinrui Yuan¹, Pan Chen², Jinpei Zhou³, Huibin Zhang⁴

Affiliations

¹ Center of Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China.
² Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
³ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: [email protected].
⁴ Center of Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: [email protected].

PMID: 30824168
DOI: 10.1016/j.bmc.2019.02.045

Abstract

BRD9 is the subunit of mammalian SWI/SNF chromatin remodeling complex (BAF). SWI/SNF complex mutations were found in nearly 20% of human cancers. The biological role played by BRD9 bromodomain remains poorly understood, and it is therefore imperative to identify potent and highly selective inhibitors to effectively explore the biology of individual bromodomain proteins. In this paper, we synthesized a series of imidazo[1,5-a]pyrazin-8(7H)-one derivatives as potent BRD9 inhibitors and evaluated their BRD9 inhibitory activity in vitro and anti-proliferation effects against tumor cells. Gratifyingly, compound 27 and 29 exhibited robust potency of BRD9 inhibition with IC₅₀ values of 35 and 103 nM respectively. Docking studies were performed to explain the structure-activity relationship. Furthermore, compound 27 potently inhibited cell proliferation in cell lines A549 and EOL-1 with an IC₅₀ value of 6.12 μM and 1.76 μM respectively. The chemical probe, compound 27, was identified that should prove to be useful in further exploring BRD9 bromodomain biology in both in vitro and in vivo settings.

Keywords: BRD9 inhibitors; Histone modifications; Molecular docking.

Publication types

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

MeSH terms

Dose-Response Relationship, Drug
Drug Design*
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / pharmacology*
Molecular Docking Simulation
Molecular Structure
Pyrazines / chemical synthesis
Pyrazines / chemistry
Pyrazines / pharmacology*
Structure-Activity Relationship
Transcription Factors / antagonists & inhibitors*
Transcription Factors / metabolism

Substances

BRD9 protein, human
Imidazoles
Pyrazines
Transcription Factors