Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders

Abstract

Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein–protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)­pyrimidin-4-yl)­amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo­[d]­imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing.

Small-molecule-induced polymerization triggers degradation of BCL6

“…BI-3802, as well as structurally related bioavailable analogs 29 , have markedly increased activity against lymphoma cells compared to BI-3812 6 , which is likely due to the combined effects of inhibiting co-activator binding, sequestering BCL6 into foci, and degrading BCL6. It has been previously shown that inhibition of BCL6 or degradation by PROTACs results in insufficient inhibition of downstream targets and consequently only minor anti-proliferative effects 5 .…”

Haven't got a glue: Protein surface variation for the design of molecular glue degraders

“…The solventexposed moiety of BI-3812 clashes with a helix of BTBb. (C) Another inhibitor-degrader pair identified for BCL6 (Bellenie et al, 2020). (D) Inhibitor and degrader of BRD4 (Blake, 2019).…”

Identification of an atypical interaction site in the BTB domain of the MYC-interacting zinc-finger protein 1

“…Based on this concept, various synthetic inhibitors of BCL6-co-repressor interactions have been developed, all of which target the lateral groove (Cardenas et al, 2016;Cerchietti et al, 2009Cerchietti et al, , 2010Cheng et al, 2018;Evans et al, 2014;Ghetu et al, 2008;Kamada et al, 2017;Kerres et al, 2017;McCoull et al, 2017;Sakamoto et al, 2017;Silva et al, 2007;Yasui et al, 2017). Certain lateral groove-binding compounds induce the ubiquitin-dependent proteasomal degradation of BCL6 in the cell (Bellenie et al, 2020;Kerres et al, 2017;S1abicki et al, 2020) while others have been utilized as building blocks for proteolysis-targeting chimeras (PROTACs) (McCoull et al, 2018). Together, these studies highlight the remarkable susceptibility of the BTB fold to smallmolecule-mediated manipulations and the intriguing potential of harnessing this susceptibility for the therapeutic targeting of transcription factors.…”