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Human HDAC isoform selectivity achieved via exploitation of the acetate release channel with structurally unique small molecule inhibitors.

Whitehead, Lewis and Vash, Brian and Dobler, Markus and Radetich, Branko and Grob, Jonathan and Mcriner, Andrew and Pancost, Margaret and Patnaik, Anup and Shao, Wenlin and Shultz, Michael and Tichkule, Ritesh and Tommasi, Ruben and Zhu, Yanyi and Wang, Ping and Atadja, Peter and Stams, Travis and Claiborne, Tavina (2011) Human HDAC isoform selectivity achieved via exploitation of the acetate release channel with structurally unique small molecule inhibitors. Bioorganic and Medicinal Chemistry.

Abstract

Herein we report the discovery of a family of simple, amino acid derived class I HDAC inhibitors. By means of traditional medicinal chemistry optimization methods in partnership with X-ray crystallography approaches and molecular modeling techniques, excellent HDAC8 selectivity was achieved. Isoform selectivity criteria is discussed on the basis of X-ray crystal structures of our novel inhibitors bound to HDAC8, marking the first reported exploitation of the HDAC acetate binding tunnel with a non-natural substrate conferring isoform selectivity.

Item Type: Article
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Keywords: Histone deacetylase, X-ray crystallography, Selectivity, acetate release hypothesis, metal binding.
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/1818

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