Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants

• Authors: MAREK Martin; SHAIK Tajith B.; HEIMBURG Tino; CHAKRABARTI Alokta; LANCELOT Julien; RAMOS-MORALES Elizabeth; DA VEIGA Cyrielle; KALININ Dmitrii; MELESINA Jelena; ROBAA Dina; SCHMIDTKUNZ Karin; SUZUKI Takayoshi; HOLL Ralph; ENNIFAR Eric; PIERCE Raymond J.; JUNG Manfred; SIPPL Wolfgang; ROMIER Christophe
• Year of publication: 2018
• Type: Article in Periodical
• Magazine / Source: Journal of Medicinal Chemistry
• MU Faculty or unit: Faculty of Science
• Web: https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01087
• Doi: http://dx.doi.org/10.1021/acs.jmedchem.8b01087
• Keywords: EFFICIENT GENERATION; SCHISTOSOMA-MANSONI; CANCER EPIGENETICS; CRYSTAL-STRUCTURE; MOLECULAR-BASIS; AM1-BCC MODEL; ACETYLATION; MECHANISM; TRANSCRIPTION; CORNELIA
• Description: Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet the currently FDA-approved HDAC inhibitors nonspecifically target at least several of the 11 structurally similar but functionally different HDAC isozymes, which hampers their broad usage in clinical settings. Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse. Here, we show that HDAC8-selective inhibitors adopt a L-shaped conformation required for their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1-L6 lock sterically prevents L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein engineering decreases potency of HDAC8-selective inhibitors and affects catalytic activity. Collectively, our results unravel key HDAC8 active site structural and functional determinants important for the design of next generation chemical probes and epigenetic drugs.