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

This dataset contains the untargeted lipidomics data for the publication Lechner et al. 2022 "Target deconvolution of the HDAC pharmacopoeia  highlights MBLAC2 as a common off-target". The dataset has also been submitted to MetaboLight repository with ID "MTBLS3557". Please refer to the MetaboLight repository for the most up-to-date datasets. 

Publication abstract:

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.

本数据集包含Lechner等人2022年发表的题为《HDAC药典靶点解析揭示MBLAC2为常见脱靶靶点》的研究中的非靶向脂质组学数据。该数据集已提交至MetaboLight数据库，编号为"MTBLS3557"，最新数据集请参阅MetaboLight数据库。

出版物摘要：

组蛋白去乙酰化酶（Histone deacetylase, HDAC）靶向药物已于21世纪初纳入药典。然而，部分不明表型提示药物存在脱靶结合现象。本研究开发了一种基于固定化HDAC抑制剂与质谱联用的定量化学蛋白质组学检测方法，用于系统绘制53种药物的靶点全景图谱。该检测方法覆盖了11种人类锌依赖型HDAC中的9种，对部分广泛使用药物（尤其是HDAC6抑制剂）的已报道选择性提出了质疑，并阐明了HDAC复合物组成如何影响药物效力。出乎意料的是，含金属β-内酰胺酶结构域蛋白2（metallo-beta-lactamase domain-containing protein 2, MBLAC2）被鉴定为羟肟酸类HDAC抑制剂的常见脱靶靶点。这种功能尚未被充分表征的棕榈酰辅酶A水解酶可被24种HDAC抑制剂以纳摩尔级低浓度抑制。MBLAC2的酶活性抑制与基因敲低均会引发细胞外囊泡蓄积。鉴于细胞外囊泡生物学在神经系统疾病与癌症中的重要性，这种不依赖HDAC的药物效应或可使MBLAC2成为药物研发的潜在靶点。