Dataset Information

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

ABSTRACT: HDAC drugs have entered the pharmacopoeia in the 2000s. However, some enigmatic phenotypes suggest off-target engagement. Here, we developed a chemical proteomics assay using three promiscuous chemotypes and quantitative mass spectrometry that we deployed to establish the target landscape of 56 HDAC drugs. The results highlight 14 direct targets, including 9 out of the 11 human zinc-dependent HDACs, question the reported selectivity of widely-used molecules, notably for HDAC6, and identified novel interactome-dependent binding of drugs to HDAC1/2 epigenetic complexes. Unexpectedly, metallo-beta-lactamase domain-containing protein 2 (MBLAC2) featured as a frequent target of hydroxamate drugs. This ill-annotated palmitoyl-CoA hydrolase is inhibited by 24 HDAC inhibitors at low nM potency. Both enzymatic inhibition and knocking down the protein led to the accumulation of extracellular vesicles. Given the importance of exosome biology in neurological diseases or cancer, this HDAC-independent drug effect creates the incentive for considering MBLAC2 as a target for drug discovery.

INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Severin Lechner

LAB HEAD: Bernhard Kuster

PROVIDER: PXD026657 | Pride | 2022-05-11

REPOSITORIES: Pride

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

Lechner Severin S Malgapo Martin Ian P MIP Grätz Christian C Steimbach Raphael R RR Baron Agnes A Rüther Patrick P Nadal Simon S Stumpf Carmen C Loos Christina C Ku Xin X Prokofeva Polina P Lautenbacher Ludwig L Heimburg Tino T Würf Vivian V Meng Chen C Wilhelm Mathias M Sippl Wolfgang W Kleigrewe Karin K Pauling Josch K JK Kramer Karl K Miller Aubry K AK Pfaffl Michael W MW Linder Maurine E ME Kuster Bernhard B Médard Guillaume G

Nature chemical biology 20220428 8

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 comp ...[more]

PMID: 35484434

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Project description:Sensing of microbial products by innate immune cells skew their transcriptional program to optimize anti-microbial defences. Chromatin remodeling by histone deacetylases (HDACs) plays a fundamental role in tailoring gene expression. HDAC inhibitors are among the most promising anti-cancer drugs and possess intrinsic anti-inflammatory properties. Yet, the influence of HDAC inhibition on innate immune responses to microbial infection is unknown. Here we show that HDAC inhibitors repress the expression of less than 10% of the genes expressed at baseline in BM-derived macrophages. In sharp contrast, HDAC inhibitors strongly interfere with transcriptome remodeling induced by LPS and Pam3CSK4, affecting the expression of 30-70% of genes modulated by microbial stimuli. Strikingly, HDAC inhibitors target the expression of numerous genes involved in anti-microbial host defences, encoding for microbial sensors, cytokines, chemokines, growth factors and their receptors, adhesion and signaling molecules, and molecules involved in antigen processing and presentation. At the molecular level, HDAC inhibitors do not impair mitogen-activated protein kinase, NF-kB, interferon-related factor signal and STAT1 transduction pathways, but inhibit NF-kB p65 recruitment to the promoter region of HDAC inhibitor-sensitive genes. HDAC inhibitors also inhibit the response of mouse and human DCs, splenocytes and whole blood to a broad range of microbial products and microorganisms. In agreement with these in vitro findings, HDAC inhibitors increase bacterial burden and sensitize mice to sub-lethal infection with Klebsiella pneumoniae and Candida albicans. Conversely, HDAC inhibitors confer protection in models of Pam3CSK4-induced fulminant toxic shock and severe sepsis following cecal ligation and puncture. Overall, these data substantiate the concept of immunomodulation by HDAC inhibitors, and suggest that these drugs could represent efficacious adjunctive therapy of severe sepsis. Mus musculus cells were grown in presence of LPS or LPS + TSA and pam or pam + TSA and hybrydised against a cRNA pool UMRR (from Mus musculus cells).

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