Target deconvolution of HDAC pharmacopoeia reveals MBLAC2 as common off-target.

Autor: Lechner S; Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Germany., Malgapo MIP; Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA., Grätz C; Animal Physiology and Immunology, TUM School of Life Sciences, Technical University of Munich, Freising, Germany., Steimbach RR; Cancer Drug Development, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany., Baron A; Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Germany., Rüther P; Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Germany., Nadal S; Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Germany., Stumpf C; Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Germany., Loos C; Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Germany., Ku X; Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Germany., Prokofeva P; Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Germany., Lautenbacher L; Computational Mass Spectrometry, TUM School of Life Sciences, Technical University of Munich, Freising, Germany., Heimburg T; Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, Halle (Saale), Germany., Würf V; LipiTUM, Chair of Experimental Bioinformatics, TUM School of Life Sciences, Technical University of Munich, Freising, Germany., Meng C; Bavarian Center for Biomolecular Mass Spectrometry (BayBioMS), Technical University of Munich, Freising, Germany., Wilhelm M; Computational Mass Spectrometry, TUM School of Life Sciences, Technical University of Munich, Freising, Germany., Sippl W; Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, Halle (Saale), Germany., Kleigrewe K; Bavarian Center for Biomolecular Mass Spectrometry (BayBioMS), Technical University of Munich, Freising, Germany., Pauling JK; LipiTUM, Chair of Experimental Bioinformatics, TUM School of Life Sciences, Technical University of Munich, Freising, Germany., Kramer K; Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Germany., Miller AK; Cancer Drug Development, German Cancer Research Center (DKFZ), Heidelberg, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany., Pfaffl MW; Animal Physiology and Immunology, TUM School of Life Sciences, Technical University of Munich, Freising, Germany., Linder ME; Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA., Kuster B; Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Germany.; Bavarian Center for Biomolecular Mass Spectrometry (BayBioMS), Technical University of Munich, Freising, Germany., Médard G; Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Germany. g.medard@tum.de.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2022 Aug; Vol. 18 (8), pp. 812-820. Date of Electronic Publication: 2022 Apr 28.
DOI: 10.1038/s41589-022-01015-5
Abstrakt: 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.
(© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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