Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, Freising, Germany.
Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
Nat Chem Biol. 2022 Aug;18(8):812-820. doi: 10.1038/s41589-022-01015-5. Epub 2022 Apr 28.
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.
靶向组蛋白去乙酰化酶（HDAC）的药物在 21 世纪初进入了药典。然而，一些神秘的表型表明存在脱靶效应。在这里，我们开发了一种使用固定化 HDAC 抑制剂和质谱的定量化学蛋白质组学测定法，用于确定 53 种药物的靶标图谱。该测定法涵盖了 11 种人类锌依赖性 HDAC 中的 9 种，质疑了一些广泛使用的分子（特别是针对 HDAC6）的报道选择性，并描述了 HDAC 复合物的组成如何影响药物效力。出乎意料的是，金属β-内酰胺酶结构域蛋白 2（MBLAC2）是羟肟酸类药物的常见脱靶蛋白。这种表征不佳的棕榈酰辅酶 A 水解酶被 24 种 HDAC 抑制剂以低纳摩尔效力抑制。MBLAC2 的酶抑制和敲低导致细胞外囊泡的积累。鉴于细胞外囊泡生物学在神经疾病和癌症中的重要性，这种 HDAC 非依赖性药物作用可能使 MBLAC2 成为药物发现的靶标。
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