Abstract
Background and Purpose: The transcription factor B cell
lymphoma 6 (BCL6) is an oncogenic driver of diffuse large B cell
lymphoma (DLBCL). 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.
Experimental Approach: 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. The binding affinity between WK500B and BCL6 was evaluated
by surface plasmon resonance (SPR) assay and the binding mode of WK500B
and BCL6 was predicted by molecular docking. The function evaluation and
anti-cancer activity of WK500B was detected by immunofluorescence assay,
Real-Time Quantitative PCR, cell proliferation assay, cell cycle assay,
cell apoptosis assay, enzyme-linked immunosorbent assay (ELISA) and
animal models.
Key Results: 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 centre (GC) formation and DLBCL tumor growth
without toxic and side effects. Moreover, WK500B showed favourable
pharmacokinetics and presented superior druggability compared to other
BCL6 inhibitors.
Conclusions and Implications: WK500B showed strong efficacy and
favourable pharmacokinetics and presented superior druggability compared
to other BCL6 inhibitors. So,
WK500B is a promising candidate
that could be developed as an effective orally available therapeutic
agent for DLBCL.
Keywords: BCL6, DLBCL, BTB domain, GC, small molecule inhibitor