Optimization of a Series of 2,3-Dihydrobenzofurans as Highly Potent, Second Bromodomain (BD2)-Selective, Bromo and Extra-Terminal Domain (BET) Inhibitors

Abstract

Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised in vitro clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor 71 (GSK852): a potent, 1000-fold-selective, highly soluble compound with good in vivo rat and dog pharmacokinetics.

Targeted protein degradation reveals BET bromodomains as the cellular target of Hedgehog Pathway Inhibitor-1

“…The protocol was adapted from Bai et al 56 . Briefly, 5000 binary complexes of the second bromodomain of BRD2 (PDB 7OE8 54 ) and cereblon E3 ligase (PDB 5FQD 68 were thalidomide from PDB 4CI12 69 replaced lenalidomide) were generated with the Rosetta software package 70 using a local docking protocol. In both proteins, the ligands (HPI-1 for BRD2 and thalidomide for cereblon) were kept and considered rigidly as part of their respective protein.…”

“…In particular, the conserved residue N429 forms the same network of H-bonds with HPI-1 as other inhibitors. [53][54][55] HPI-1 interacts via a T-shaped π-π stacking with tryptophan 370 (W370) and one of its carbonyl groups binds to histidine 433 (H433) being the H-bond donor. This last interaction might explain the difference in affinity between the second and the first bromodomain of BRD2, where histidine is replaced by an aspartate, abrogating this predicted H-bond.…”

“…The crystal structure of the second bromodomain of BRD2 was downloaded from the Protein Data Bank (PDB code 7OE8 54 ). The protein was then prepared with Maestro release 2021-1 (Schrödinger, LLC, New York, NY, 2021).…”

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.…”

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. The first developed selective compounds were BDI selective, the most extensively studied are olinone 28 , MS402 29 , and GSK778 30 .…”