Design and Synthesis of Simplified Largazole Analogues as Isoform-Selective Human Lysine Deacetylase Inhibitors

Damodara N. Reddy, Flavio Ballante, Timothy Chuang, Adele Pirolli, Biagina Marrocco, Garland R. Marshall

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1613-1633
Number of pages21
JournalJournal of Medicinal Chemistry
Volume59
Issue number4
DOIs
StatePublished - Feb 25 2016

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