| Literature DB >> 35484434 |
Severin Lechner1, Martin Ian P Malgapo2, Christian Grätz3, Raphael R Steimbach4,5, Agnes Baron1, Patrick Rüther1, Simon Nadal1, Carmen Stumpf1, Christina Loos1, Xin Ku1, Polina Prokofeva1, Ludwig Lautenbacher6, Tino Heimburg7, Vivian Würf8, Chen Meng9, Mathias Wilhelm6, Wolfgang Sippl7, Karin Kleigrewe9, Josch K Pauling8, Karl Kramer1, Aubry K Miller4,10, Michael W Pfaffl3, Maurine E Linder2, Bernhard Kuster1,9, Guillaume Médard11.
Abstract
Drugs that target histone deacetylase (HDAC) 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-β-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 nanomolar potency. MBLAC2 enzymatic inhibition and knockdown 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.Entities:
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Year: 2022 PMID： 35484434 PMCID： PMC9339481 DOI： 10.1038/s41589-022-01015-5
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 16.174