Progress toward B-Cell Lymphoma 6 BTB Domain Inhibitors for the Treatment of Diffuse Large B-Cell Lymphoma and Beyond

Abstract

B-cell lymphoma 6 (BCL6) is a master regulator of germinal center formation that produce antibody-secreting plasma cells and memory B-cells for sustained immune responses. The BTB domain of BCL6 (BCL6BTB) forms a homodimer that mediates transcriptional repression by recruiting its corepressor proteins to form a biologically functional transcriptional complex. The protein–protein interaction (PPI) between the BCL6BTB and its corepressors has emerged as a therapeutic target for the treatment of DLBCL and a number of other human cancers. This Perspective provides an overview of recent advances in the development of BCL6BTB inhibitors from reversible inhibitors, irreversible inhibitors, to BCL6 degraders. Inhibitor design and medicinal chemistry strategies for the development of novel compounds will be provided. The binding mode of new inhibitors to BCL6BTB are highlighted. Also, the in vitro and in vivo assays used for the evaluation of new compounds will be discussed.

Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors

“…Although our previous lead inhibitor 3 showed a >20-fold drop-off, 1 shows ∼3-fold from 3.9 nM (TR-FRET) to 12 nM (NanoBRET). We speculate that this discrepancy could result from differences in binding to the TR-FRET assay construct (BTB domain) and full length BCL6 used in the nanoBRET: this hypothesis has been previously proposed to explain mismatches between cell-free and cellular assays for a different series of BCL6 inhibitors . The improved cellular potency of 1 translates into increased antiproliferative activity in BCL6-high OCI-Ly1 and Karpas-422 cell lines, and selectivity over the BCL6-low OCI-Ly3 line is maintained (Table ).…”

“…We speculate that this discrepancy could result from differences in binding to the TR-FRET assay construct (BTB domain) and full length BCL6 used in the nanoBRET: this hypothesis has been previously proposed to explain mismatches between cell-free and cellular assays for a different series of BCL6 inhibitors. 26 The improved cellular potency of 1 translates into increased antiproliferative activity in BCL6-high OCI-Ly1 and Karpas-422 cell lines, and selectivity over the BCL6-low OCI-Ly3 line is maintained ( Table 4 ). With improved potency, a reduced molecular weight and polar surface area, and hence an increased ligand efficiency compared to 3 ( Table 4 ), compound 1 (CCT372064) represents a new core structure for further elaboration toward the identification of candidate-quality BCL6 inhibitors; a subsequent publication will describe how this new core enabled the discovery of more potent, in vivo active degraders of BCL6.…”

[Retracted] Analysis of the Correlation of Basic Fibroblast Growth Factor in Serum of Patients with Diffuse Large B‐Cell Lymphoma with Clinicopathological Efficacy and International Prognostic Index

“…DLBCL is a common clinical invasive tumor with complex clinical manifestations, which endangers people's health [6].…”

Molecular glues modulate protein functions by inducing protein aggregation: A promising therapeutic strategy of small molecules for disease treatment

“…B-cell lymphoma 6 (BCL6), a transcriptional repressor protein, is a potential drug target for non-Hodgkin's lymphoma 47 , 48 . Several small molecule inhibitors and peptides of BCL6 with in vivo efficacy can only work at high concentrations, limiting their clinical application 49 , 50 , 51 .…”