An orally available small molecule BCL6 inhibitor effectively suppresses diffuse large B cell lymphoma cells growth in vitro and in vivo

Yajing Xing; Weikai Guo; Min Wu; Jiuqing Xie; Dongxia Huang; Pan Hu; Miaoran Zhou; Lin Zhang; Qiansen Zhang; Peili Wang; Xin Wang; Guixue Wang; Huangan Wu; Cili Zhou; Yihua Chen; Mingyao Liu; Zhengfang Yi; Zhenliang Sun

doi:10.1016/j.canlet.2021.12.035

An orally available small molecule BCL6 inhibitor effectively suppresses diffuse large B cell lymphoma cells growth in vitro and in vivo

Cancer Lett. 2022 Mar 31:529:100-111. doi: 10.1016/j.canlet.2021.12.035. Epub 2022 Jan 4.

Authors

Yajing Xing¹, Weikai Guo², Min Wu², Jiuqing Xie², Dongxia Huang², Pan Hu², Miaoran Zhou³, Lin Zhang², Qiansen Zhang², Peili Wang², Xin Wang², Guixue Wang⁴, Huangan Wu³, Cili Zhou³, Yihua Chen², Mingyao Liu⁵, Zhengfang Yi⁶, Zhenliang Sun⁷

Affiliations

¹ East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai University of Medicine & Health Sciences Affiliated Sixth People's Hospital South Campus, 201499, Shanghai, China; Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, 400030, China.
² East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai University of Medicine & Health Sciences Affiliated Sixth People's Hospital South Campus, 201499, Shanghai, China.
³ Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
⁴ Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, 400030, China.
⁵ East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai University of Medicine & Health Sciences Affiliated Sixth People's Hospital South Campus, 201499, Shanghai, China; East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
⁶ East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai University of Medicine & Health Sciences Affiliated Sixth People's Hospital South Campus, 201499, Shanghai, China; East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China. Electronic address: zfyi@bio.ecnu.edu.cn.
⁷ East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai University of Medicine & Health Sciences Affiliated Sixth People's Hospital South Campus, 201499, Shanghai, China; East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China. Electronic address: zhenliang@smu.edu.cn.

PMID: 34990752
DOI: 10.1016/j.canlet.2021.12.035

Abstract

The transcription factor B cell lymphoma 6 (BCL6) is an oncogenic driver of diffuse large B cell lymphoma (DLBCL) and mediates lymphomagenesis through transcriptional repression of its target genes by recruiting corepressors to its N-terminal broad-complex/tramtrack/bric-a-brac (BTB) domain. Blocking the protein-protein interactions of BCL6 and its corepressors has been proposed as an effective approach for the treatment of DLBCL. However, BCL6 inhibitors with excellent drug-like properties are rare. Hence, the development of BCL6 inhibitors is worth pursuing. We screened our internal chemical library by luciferase reporter assay and Homogenous Time Resolved Fluorescence (HTRF) assay and a small molecule compound named WK500B was identified. WK500B engaged BCL6 inside cells, blocked BCL6 repression complexes, reactivated BCL6 target genes, killed DLBCL cells and caused apoptosis as well as cell cycle arrest. In animal models, WK500B inhibited germinal center (GC) formation and DLBCL tumour growth without toxic and side effects. Moreover, WK500B displayed strong efficacy and favourable pharmacokinetics and presented superior druggability. Therefore, WK500B is a promising candidate that could be developed as an effective orally available therapeutic agent for DLBCL.

Keywords: BCL6 inhibitor; BTB domain; Diffuse large B cell Lymphoma; Germinal center.

Publication types

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

MeSH terms

Animals
Apoptosis / drug effects
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Synergism
Genes, Reporter
Germinal Center / drug effects
Germinal Center / immunology
Germinal Center / metabolism
Humans
Lymphoma, Large B-Cell, Diffuse
Mice
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-bcl-6 / antagonists & inhibitors*
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

BCL6 protein, human
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-bcl-6