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

• Published in: Cancer letters Vol. 529; pp. 100 - 111
• Main Authors: Xing, Yajing, Guo, Weikai, Wu, Min, Xie, Jiuqing, Huang, Dongxia, Hu, Pan, Zhou, Miaoran, Zhang, Lin, Zhang, Qiansen, Wang, Peili, Wang, Xin, Wang, Guixue, Wu, Huangan, Zhou, Cili, Chen, Yihua, Liu, Mingyao, Yi, Zhengfang, Sun, Zhenliang
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 31.03.2022; Elsevier Limited
• Subjects: Animal models; Animals; Apoptosis; Apoptosis - drug effects; Bcl-6 protein; BCL6 inhibitor; BTB domain; Cell cycle; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Diffuse large B cell Lymphoma; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Gene silencing; Genes, Reporter; Germinal center; Germinal Center - drug effects; Germinal Center - immunology; Germinal Center - metabolism; Humans; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Mice; Models, Molecular; Molecular Structure; Mutation; Peptides; Pharmacokinetics; Protein interaction; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proteins; Proto-Oncogene Proteins c-bcl-6 - antagonists & inhibitors; Structure-Activity Relationship; Tumors; Xenograft Model Antitumor Assays; United States > US; BTB domain; BCL6 inhibitor; Diffuse large B cell Lymphoma; Germinal center
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2021.12.035

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. •WK500B exhibits potent efficacy against DLBCL in vitro and in vivo.•WK500B shows favourable pharmacokinetic and presents superior druggability.•WK500B could be a promising therapeutic drug candidate for DLBCL.