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