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

journal contribution
posted on 2023-06-08, 14:44 authored by Ming-Qiang Zhang, Sabine Gaisser, Mohammad Nur-E-Alam, Lesley S Sheehan, William A Vousden, Nikolaos Gaitatzis, Gerrard Peck, Nigel J Coates, Steven J Moss, Markus Radzom, Teresa A Foster, Rose M Sheridan, Matthew A Gregory, Susan M Roe, Chrisostomos ProdromouChrisostomos Prodromou, Laurence PearlLaurence Pearl, Susan M Boyd, Barrie Wilkinson, Christine J Martin
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.

History

Publication status

  • Published

Journal

Journal of Medicinal Chemistry

ISSN

0022-2623

Publisher

American Chemical Society

Issue

18

Volume

51

Page range

5494-5497

Department affiliated with

  • Biochemistry Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2015-02-24