2. Academic Validation
  3. Groebke Blackburn Bienaymé-mediated multi-component synthesis of selective HDAC6 inhibitors with anti-inflammatory properties

Groebke Blackburn Bienaymé-mediated multi-component synthesis of selective HDAC6 inhibitors with anti-inflammatory properties

  • Bioorg Chem. 2024 Feb:143:107072. doi: 10.1016/j.bioorg.2023.107072.
Fabian B Kraft 1,  Jana Enns 2,  Irina Honin 1,  Jonas Engelhardt 2,  Andrea Schöler 3,  Shannon T Smith 4,  Jens Meiler 5,  Linda Schäker-Hübner 1,  Günther Weindl 2,  Finn K Hansen 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
  • 2 Department of Pharmacology and Toxicology, Pharmaceutical Institute, University of Bonn, Gerhard-Domagk-Str.3, 53121 Bonn, Germany.
  • 3 Institute for Drug Discovery, Medicinal Faculty, University Leipzig, Brüderstraße 34, 04103 Leipzig, Germany.
  • 4 Center for Structural Biology, Vanderbilt University, Nashville, TN 37240, USA.
  • 5 Institute for Drug Discovery, Medicinal Faculty, University Leipzig, Brüderstraße 34, 04103 Leipzig, Germany; Center for Structural Biology, Vanderbilt University, Nashville, TN 37240, USA.
  • 6 Department of Pharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany. Electronic address: [email protected].
PMID: 38185013 DOI: 10.1016/j.bioorg.2023.107072
Abstract

Histone deacetylases (HDACs) are a class of enzymes that cleave acyl groups from lysine residues of histone and non-histone proteins. There are 18 human HDAC isoforms with different cellular targets and functions. Among them, HDAC6 was found to be overexpressed in different types of Cancer. However, when used in monotherapy, HDAC6 inhibition by selective inhibitors fails to show pronounced anti-cancer effects. The HDAC6 Enzyme also addresses non-histone proteins like α-tubulin and cortactin, making it important for cell migration and angiogenesis. Recently, the NLRP3 inflammasome was identified as an important regulator of inflammation and immune responses and, importantly, HDAC6 is critically involved the activation of the inflammasome. We herein report the design, synthesis and biological evaluation of a library of selective HDAC6 inhibitors. Starting from the previously published crystal structure of MAIP-032 in complex with CD2 of zHDAC6, we performed docking studies to evaluate additional possible interactions of the cap group with the L1-loop pocket. Based on the results we synthesized 13 novel HDAC6 inhibitors via the Groebke-Blackburn-Bienaymé three component reaction as the key step. Compounds 8k (HDAC1 IC50: 5.87 μM; HDAC6 IC50: 0.024 μM; selectivity factor (SF1/6): 245) and 8m (HDAC1 IC50: 3.07 μM; HDAC6 IC50: 0.026 μM; SF1/6: 118) emerged as the most potent and selective inhibitors of HDAC6 and outperformed the lead structure MAIP-032 (HDAC1 IC50: 2.20 μM; HDAC6 IC50: 0.058 μM; SF1/6: 38) both in terms of inhibitory potency and selectivity. Subsequent immunoblot analysis confirmed the high selectivity of 8k and 8m for HDAC6 in a cellular environment. While neither 8k and 8m nor the selectivity HDAC6 Inhibitor tubastatin A showed antiproliferative effects in the U-87 MG glioblastoma cell line, compound 8m attenuated cell migration significantly in wound healing assays in U-87 MG cells. Moreover, in macrophages compounds 8k and 8m demonstrated significant inhibition of LPS-induced IL1B mRNA expression and TNF release. These findings suggest that our imidazo[1,2-a]pyridine-capped HDAC6 inhibitors may serve as promising candidates for the development of drugs to effectively treat NLRP3 inflammasome-driven inflammatory diseases.

Keywords

Cancer; HDAC6; Histone deacetylase; Inflammation; NLRP3 inflammasome.

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