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Published on: October 5, 2012
An orally available small molecule BCL6 inhibitor effectively suppresses diffuse large B cell lymphoma cells growth
Yajing Xing1, Weikai Guo2, Min Wu2
1East 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.
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.
Insights
A new compound, WK500B, effectively targets B cell lymphoma 6 (BCL6) in diffuse large B cell lymphoma (DLBCL). This drug candidate inhibits tumor growth and shows promise for oral therapy with minimal side effects.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- B cell lymphoma 6 (BCL6) is a key oncogenic driver in diffuse large B cell lymphoma (DLBCL).
- BCL6 functions by recruiting corepressors via its BTB domain, leading to transcriptional repression.
- Targeting BCL6-corepressor interactions is a potential therapeutic strategy for DLBCL, but suitable inhibitors are scarce.
Purpose of the Study:
- To identify and characterize novel small molecule inhibitors of BCL6.
- To evaluate the therapeutic potential of identified inhibitors in DLBCL models.
Main Methods:
- Screening of an internal chemical library using luciferase reporter and HTRF assays.
- In vitro assays to assess BCL6 engagement, target gene reactivation, and DLBCL cell killing (apoptosis, cell cycle arrest).
- In vivo studies in animal models to evaluate anti-tumor efficacy and toxicity.
Main Results:
- Identification of WK500B as a potent BCL6 inhibitor.
- WK500B demonstrated cellular activity by blocking BCL6 repression complexes and reactivating target genes.
- WK500B induced DLBCL cell death, apoptosis, and cell cycle arrest.
- In vivo, WK500B inhibited germinal center formation and DLBCL tumor growth without observable toxic effects.
- WK500B exhibited favorable pharmacokinetics and druggability.
Conclusions:
- WK500B effectively inhibits BCL6 activity and demonstrates anti-DLBCL efficacy in preclinical models.
- WK500B shows promise as an orally available therapeutic agent for DLBCL treatment.
- Further development of WK500B is warranted due to its strong efficacy and favorable drug-like properties.
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