Format

Send to

Choose Destination
J Med Chem. 2016 Feb 25;59(4):1613-33. doi: 10.1021/acs.jmedchem.5b01632. Epub 2016 Jan 7.

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

Author information

1
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine , 700 South Euclid Avenue, St. Louis, Missouri 63110, United States.
2
Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma , P. le A. Moro 5, 00185 Roma, Italy.
3
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma , P. le A. Moro 5, 00185 Roma, Italy.

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.

PMID:
26681404
DOI:
10.1021/acs.jmedchem.5b01632
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for American Chemical Society
Loading ...
Support Center