GNE-235: A Lead Compound Selective for the Second Bromodomain of PBRM1

Abstract

Bromodomains are acetyl-lysine binding modules that are found in different classes of chromatin-interacting proteins. Among these are large chromatin remodeling complexes such as BAF and PBAF (variants of human SWI/SNF). Previous work has identified chemical probes targeting a subset of the bromodomains present in the BAF and PBAF complexes. Selective inhibitors of the individual bromodomains have proven challenging to discover, as the domains are highly similar. Here, elaboration of an aminopyridazine scaffold used previously to develop probes for the bromodomains of SMARCA2, SMARCA4, and the fifth bromodomain of PBRM1 yielded compounds with both potency and unusual selectivity for the second bromodomain of PBRM1. One of these, GNE-235, and its enantiomer control GNE-234 are suggested for initial cellular investigations of the function of the second bromodomain of PBRM1.

Targeting SWI/SNF Complexes in Cancer: Pharmacological Approaches and Implications

“…Family VIII inhibitors that are selective for PBRM1 bromodomains over those of SMARCA4 and SMARCA2 have also been developed and studied for anti-cancer effects [163][164][165]. Although a tumor suppressor in some cancers [166], PBRM1 promotes prostate cancer growth and progression [167,168].…”

“…These drugs effectively inhibited the proliferation of an androgen receptor (AR)-positive prostate cancer cell line, with the most potent compound, PB16, exerting its effects in the sub-micromolar range. GNE-235 is a promising new PBRM1-selective inhibitor that has not yet been tested for its anti-tumor effects [165]. The promising results obtained with PB16 suggest that GNE-235 and other PBRM1-selective inhibitors should be further explored for anti-cancer effects as single drugs and in combination with DNA damaging agents and checkpoint inhibitors.…”

“…The anti-cancer effects of Class VIII SWI/SNF bromodomain inhibitors can be enhanced by linking the bromodomain-binding ligand to an E3 ligase-binding ligand [102,165,169]. These PROTACs expand the anti-cancer effects of bromodomain inhibitors by degrading the bromodomain-containing subunits and taking them out of action.…”