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Design and Synthesis of Simplified Largazole Analogues as Isoform-Selective Human Lysine Deacetylase Inhibitors.
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 700 South Euclid Avenue, St. Louis, Missouri 63110, United States.
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 700 South Euclid Avenue, St. Louis, Missouri 63110, United States.ORCID iD: 0000-0002-4831-3423
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 700 South Euclid Avenue, St. Louis, Missouri 63110, United States.
Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita ̀ di Roma, P. le A. Moro 5, 00185 Roma, Italy.
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2016 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 4, 1613-33 p.Article in journal (Refereed) Published
Abstract [en]

Selective inhibition of KDAC isoforms while maintaining potency remains a challenge. Using the largazole macrocyclic depsipeptide structure as a starting point for developing new KDACIs with increased selectivity, a combination of four different simplified largazole analogue (SLA) scaffolds with diverse zinc-binding groups (for a total of 60 compounds) were designed, synthesized, and evaluated against class I KDACs 1, 3, and 8, and class II KDAC6. Experimental evidence as well as molecular docking poses converged to establish the cyclic tetrapeptides (CTPs) as the primary determinant of both potency and selectivity by influencing the correct alignment of the zinc-binding group in the KDAC active site, providing a further basis for developing new KDACIs of higher isoform selectivity and potency.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016. Vol. 59, no 4, 1613-33 p.
Keyword [en]
HDAC; KDAC; Largazole; in vitro Assays; Structure Based Drug Design; 3D QSAR
National Category
Medicinal Chemistry Chemical Sciences Biological Sciences Computer and Information Science
Identifiers
URN: urn:nbn:se:uu:diva-321299DOI: 10.1021/acs.jmedchem.5b01632PubMedID: 26681404OAI: oai:DiVA.org:uu-321299DiVA: diva2:1095264
Available from: 2017-05-12 Created: 2017-05-12 Last updated: 2017-05-12

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Ballante, Flavio
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