Target deconvolution of the HDAC pharmacopoeia highlights MBLAC2 as a common off-target

<p>This dataset&nbsp;contains the untargeted lipidomics data for the publication Lechner et al. 2022 &quot;Target deconvolution of the HDAC pharmacopoeia &nbsp;highlights MBLAC2 as a common off-target&quot;. The dataset has also been submitted to&nbsp;MetaboLight repository with ID &quot;MTBLS3557&quot;. Please refer to the MetaboLight repository for the most up-to-date datasets.&nbsp;</p> <p>Publication abstract:</p> <p>Histone deacetylase (HDAC) targeting drugs have entered the pharmacopoeia in the 2000s. However, some enigmatic phenotypes suggest off-target engagement. Here, we developed a quantitative chemical proteomics assay using immobilized HDAC inhibitors and mass spectrometry that we deployed to establish the target landscape of 53 drugs. The assay covers 9 of the 11 human zinc dependent HDACs, questions the reported selectivity of some widely-used molecules, notably for HDAC6, and delineates how the composition of HDAC complexes influences drug potency. Unexpectedly, metallo-beta-lactamase domain-containing protein 2 (MBLAC2) featured as a frequent off-target of hydroxamate drugs. This poorly characterized palmitoyl-CoA hydrolase is inhibited by 24 HDAC inhibitors at low nM potency. MBLAC2 enzymatic inhibition and knock down led to the accumulation of extracellular vesicles. Given the importance of extracellular vesicle biology in neurological diseases and cancer, this HDAC-independent drug effect may qualify MBLAC2 as a target for drug discovery.</p>