Discovery of selective BPTF bromodomain inhibitors by screening and structure-based optimization

Liang Xiong; Xin Mao; Yinping Guo; Yangli Zhou; Mingxin Chen; Pei Chen; Shengyong Yang; Linli Li

doi:10.1016/j.bbrc.2021.01.067

Discovery of selective BPTF bromodomain inhibitors by screening and structure-based optimization

Biochem Biophys Res Commun. 2021 Mar 19:545:125-131. doi: 10.1016/j.bbrc.2021.01.067. Epub 2021 Feb 3.

Authors

Liang Xiong¹, Xin Mao¹, Yinping Guo¹, Yangli Zhou¹, Mingxin Chen¹, Pei Chen², Shengyong Yang¹, Linli Li³

Affiliations

¹ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People's Republic of China.
² Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, People's Republic of China.
³ Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, People's Republic of China. Electronic address: lilinli@scu.edu.cn.

PMID: 33548625
DOI: 10.1016/j.bbrc.2021.01.067

Abstract

Bromodomain and PHD finger containing transcription factor (BPTF) is a multidomain protein that regulates the transcription of chromatin and is related to many cancers. Herein, we report the screening-based discovery of Cpd1, a compound with micromolar affinity to the BPTF bromodomain. Through structure-guided optimization, we synthesized a variety of new inhibitors. Among these compounds, Cpd8 and Cpd10 were highly potent and selective inhibitors, with K_D values of 428 nM and 655 nM in ITC assays, respectively. The high activity was explained by the cocrystal structure of Cpd8 in complex with the BPTF bromodomain protein. Cpd8 and Cpd10 were able to stabilize the BPTF bromodomain protein in cells in a cellular thermal shift assay (CETSA). Cpd8 downregulated c-MYC expression in A549 cells. All experiments prove that these two compounds are potential BPTF inhibitors.

Keywords: BPTF; Bromodomain; Epigenetics; Inhibitors; Structure-based optimization.

Publication types

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

MeSH terms

A549 Cells
Antigens, Nuclear / chemistry
Antigens, Nuclear / genetics
Calorimetry
Crystallography, X-Ray
Drug Design
Drug Discovery
Drug Evaluation, Preclinical
Fluorometry
Gene Expression Regulation / drug effects
Genes, myc
HEK293 Cells
Humans
Models, Molecular
Nerve Tissue Proteins / antagonists & inhibitors*
Nerve Tissue Proteins / chemistry
Nerve Tissue Proteins / genetics
Peptide Fragments / antagonists & inhibitors
Peptide Fragments / chemistry
Peptide Fragments / genetics
Protein Domains
Protein Stability / drug effects
RNA, Messenger / genetics
RNA, Messenger / metabolism
Recombinant Proteins / chemistry
Recombinant Proteins / drug effects
Recombinant Proteins / genetics
Structure-Activity Relationship
Transcription Factors / antagonists & inhibitors*
Transcription Factors / chemistry
Transcription Factors / genetics

Substances

Antigens, Nuclear
Nerve Tissue Proteins
Peptide Fragments
RNA, Messenger
Recombinant Proteins
Transcription Factors
fetal Alzheimer antigen