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

Abstract

Background: 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.Methods: 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 identi ed.The binding a nity 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 in vitro and in vivo was detected by immuno uorescence assay, Real-Time Quantitative PCR, cell proliferation assay, cell cycle assay, cell apoptosis assay, enzymelinked immunosorbent assay (ELISA), germinal centre (GC) formation mouse model and mouse xenograft model.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 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: WK500B showed strong e cacy 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.

Targeting key proteins involved in transcriptional regulation for cancer therapy: Current strategies and future prospective

“…Recently, a highly potent N-phenyl-4-pyrimidinamine-derivate BCL6 inhibitor was reported by our laboratory with excellent druggabilities and favorable pharmacokinetics. 205 This compound is expected to be developed as an orally available anticancer agent in clinical trials for the treatment of DLBCL.…”

“…Moreover, compound 14j potently inhibited the proliferation of DLBCL cells in vitro and clearly inhibited tumor growth in a DLBCL xenograft model. Recently, a highly potent N‐phenyl‐4‐pyrimidinamine‐derivate BCL6 inhibitor was reported by our laboratory with excellent druggabilities and favorable pharmacokinetics 205 . This compound is expected to be developed as an orally available anticancer agent in clinical trials for the treatment of DLBCL.…”

B-cell Lymphoma 6 Inhibitors: Current Advances and Prospects of Drug Development for Diffuse Large B-cell Lymphomas

“…Further, more than 500 diaminopyrimidine-containing compounds was performed in preliminary luciferase reporter assay to obtain compounds with significant BCL6 transcriptional repressor activity. 108 The binding affinity of these compounds with BCL6 was further analyzed by HTRF analysis, and 13 (WK500B) exhibited the strongest inhibitory activity and then the HTRF assay suggested an IC 50 of 1.39 μM, 27-fold superior to the positive control 7 (Scheme 2B). Subsequently, it was confirmed that 13 specifically bound to the BCL6 BTB domain in a dose-dependent manner.…”

BCL6 is a context-dependent mediator of the glioblastoma therapy response

“…299 While many of these inhibitors show great promise for the treatment of lymphoma, none have yet progressed to clinical trials. Xing et al (2022) commented that this may be due to the relatively weak activity of 79-6 and FX1, while higher affinity compounds developed subsequently have not been studied in vivo, possibly because their chemical properties make them unsuitable for use as drugs. 300 Xing et al went on to develop the small molecule BCL6 inhibitor WK500B which they showed to be effective and orally bioavailable in mice.…”

“…Xing et al (2022) commented that this may be due to the relatively weak activity of 79-6 and FX1, while higher affinity compounds developed subsequently have not been studied in vivo, possibly because their chemical properties make them unsuitable for use as drugs. 300 Xing et al went on to develop the small molecule BCL6 inhibitor WK500B which they showed to be effective and orally bioavailable in mice. 300 This indicates that with some further development, BCL6 inhibitors will be able to progress to clinical trials.…”