Fragment-based Scaffold Hopping: Identification of Potent, Selective, and Highly Soluble Bromo and Extra Terminal Domain (BET) Second Bromodomain (BD2) Inhibitors

Abstract

The profound efficacy of pan-BET inhibitors is well documented, but these epigenetic agents have shown pharmacology-driven toxicity in oncology clinical trials. The opportunity to identify inhibitors with an improved safety profile by selective targeting of a subset of the eight bromodomains of the BET family has triggered extensive medicinal chemistry efforts. In this article, we disclose the identification of potent and selective drug-like pan-BD2 inhibitors such as pyrazole 23 (GSK809) and furan 24 (GSK743) that were derived from the pyrrole fragment 6. We transpose the key learnings from a previous pyridone series (GSK620 2 as a representative example) to this novel class of inhibitors, which are characterized by significantly improved solubility relative to our previous research.

CRCM5484: A BET- BDII Selective Compound With Differential Anti-Leukemic Drug Modulation

“…Indeed, only one related compound could be identified for this chemical scaffold in the literature as a BD binder in one crystal structure deposited in the PDB in 2016 (PDB ID: 4ZW1), but there was no follow-up study or publication exploiting these data (Figure S3A). The other identified compounds, a dimethyl isoxazole core of 2, 3 and 4, has already been described in the BD inhibitor I-BET-151 25 or GSK778 30 , and the trimethoxyphenyl core of 5 is found in DC-BD-03 38 (Figure S2B). These results demonstrate the potential of the Fr-PPIChem chemical library to identify a new chemical core during a screening campaign.…”

“…MYC gene expression profile was also similar for these cell lines (Figure S6B). As BDII inhibition was recently shown to modulate the inflammatory stimulation of gene transcription in MHC-I antigen presentation pathway gene components 25 , we also evaluated the impact of CRCM5484 on K-562 leukemic cells stimulated with the proinflammatory cytokine interferon- γ (IFN γ ). As recently reported, the pan-BET inhibitor totally prevented IFN γ -induced expression of MHC-I while CRCM5484 partially inhibited this induction in a concentration-dependent manner, with a similar efficiency to GSK046 and in agreement with Gilan et al 30 (Figure 4C).…”

“…Despite a high homology across the BDs in the BET family, several selective inhibitors of the BDI or BDII BET domains have recently emerged in the literature [24][25][26][27] , but few are currently engaged in clinical trials. The first developed selective compounds were BDI selective, the most extensively studied are olinone 28 , MS402 29 , and GSK778 30 .…”

Virtual Special Issue: Epigenetics 2022

“…The maturity of the bromodomain and extraterminal domain (BET) proteins as targets is reflected by the reports of pan-BET ligands developed for clinical studies . In addition, there are reports of ligands that are selective for either the first or second bromodomains of these proteins and their use as tools to selectively probe the function of these bromodomains. The use of a PET radiotracer for imaging has been applied to studying the distribution of BET proteins in mice brains .…”

CRCM5484: A BET-BDII Selective Compound with Differential Anti-leukemic Drug Modulation

“…Despite a high homology across the BDs in the BET family, several selective inhibitors of the BDI or BDII BET domains have recently emerged in the literature [24][25][26][27] , but few are currently engaged in clinical trials.…”