MS645, a Bivalent BET BrD Inhibitor, Inhibits BRD4 Transcriptional Activity

Bromodomains (BrDs) in transcription proteins bind acetyl-lysine in histones and transcription factors to direct gene transcription in biology and disease conditions.  BRD4 contains two characteristic tandem BrDs. Meanwhile, BRD4 is a major drug target owing to its implicated functions in oncogenesis and inflammation. BET protein BRD4 in gene transcription is important. The study of chemical modulation of its characteristic tandem bromodomain binding to lysine-acetylated histones and transcription factors shows this. MS645 is a thienodiazepine-based bivalent BrD inhibitor. It affords spatially constrained tandem BrD inhibition, and consequently sustaines repression of BRD4 transcriptional activity in blocking proliferation of solid-tumor cells including a panel of TNBC cells. Furthermore, MS645 blocks BRD4 binding to transcription enhancer/mediator proteins MED1 and YY1. It results in down-regulation of proinflammatory cytokines and genes for cell-cycle control and DNA damage repair.

MS645 binding to the BD1 tends to affect domain-domain orientation of the tandem module. MS645 binds to the BD1 or the tandem BD1-BD2 in a stoichiometric manner. Furthermore, MS645 appears to have a clear advantage over panobinostat, as the latter is rather toxic as shown with macrophage RAW cells. MS645 not only dissociates BRD4 but also MED1 from CDK6, RAD51, and BRCA1 gene loci. Moreover, MS645 inhibits BRD4 association with MED1 or transcription factor YY1. All in all, MS645 effectively inhibits TNBC cell growth through its sustained inhibition of BRD4 activity in transcriptional activation of genes of key cellular pathways. It includes cell-cycle control and DNA damage repair required to sustain cancer cell rapid growth.

In summary, the bivalent BET BrD inhibitor MS645 affords a sustained inhibition of BRD4. It blocks BRD4 interactions with transcription enhancer/mediator proteins MED1 and YY1.  They are important for accelerated proliferation of solid-tumor TNBC cells.

Reference:

Ren C, et al.Proc Natl Acad Sci U S A. 2018 Jul 31;115(31):7949-7954.

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