Optimizing natural products by biosynthetic engineering: discovery of nonquinone Hsp90 inhibitors

Zhang, Ming-Qiang, Gaisser, Sabine, Nur-E-Alam, Mohammad, Sheehan, Lesley S, Vousden, William A, Gaitatzis, Nikolaos, Peck, Gerrard, Coates, Nigel J, Moss, Steven J, Radzom, Markus, Foster, Teresa A, Sheridan, Rose M, Gregory, Matthew A, Roe, Susan M, Prodromou, Chrisostomos, Pearl, Laurence, Boyd, Susan M, Wilkinson, Barrie and Martin, Christine J (2008) Optimizing natural products by biosynthetic engineering: discovery of nonquinone Hsp90 inhibitors. Journal of Medicinal Chemistry, 51 (18). pp. 5494-5497. ISSN 0022-2623

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Abstract

A biosynthetic medicinal chemistry approach was applied to the optimization of the natural product Hsp90 inhibitor macbecin. By genetic engineering, mutants have been created to produce novel macbecin analogues including a nonquinone compound (5) that has significantly improved binding affinity to Hsp90 (Kd 3 nM vs 240 nM for macbecin) and reduced toxicity (MTD > or = 250 mg/kg). Structural flexibility may contribute to the preorganization of 5 to exist in solution in the Hsp90-bound conformation.

Item Type: Article
Keywords: Benzoquinones/chemistry/metabolism/*pharmacology Biological Agents/chemistry/metabolism/*pharmacology *Genetic Engineering HSP90 Heat-Shock Proteins/*antagonists & inhibitors/metabolism Lactams, Macrocyclic/chemistry/metabolism/*pharmacology Molecular Sequence Data Molecular Structure
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QD Chemistry > QD0901 Crystallography
Depositing User: Chrisostomos Prodromou
Date Deposited: 24 Feb 2015 15:04
Last Modified: 24 Feb 2015 15:04
URI: http://sro.sussex.ac.uk/id/eprint/44392
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