Serendipitous and Systematic Chemoproteomic Discovery of MBLAC2, HINT1, and NME1-4 Inhibitors from Histone Deacetylase-Targeting Pharmacophores.

ABSTRACT: Metalloenzyme inhibitors often incorporate a hydroxamic acid moiety to bind the bivalent metal ion cofactor within the enzyme's active site. Recently, inhibitors of Zn²⁺-dependent histone deacetylases (HDACs), including clinically advanced drugs, have been identified as potent inhibitors of the metalloenzyme MBLAC2. However, selective chemical probes for MBLAC2, which are essential for studying its inhibitory effects, have not yet been reported. To discover highly selective MBLAC2 inhibitors, we conducted chemoproteomic target deconvolution and selectivity profiling of a library of hydroxamic acid-type molecules and other metal-chelating compounds. This screen revealed MBLAC2 as a frequent off-target of supposedly selective HDAC inhibitors, including the HDAC6 inhibitor SW-100.

SUBMITTER: Lechner S 

PROVIDER: S-EPMC12186257 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature