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

被引：65

作者：

Zhang, Ming-Qiang ^{[1
]}

Gaisser, Sabine ^{[1
]}

Nur-E-Alam, Mohammad ^{[1
]}

Sheehan, Lesley S. ^{[1
]}

Vousden, William A. ^{[1
]}

Gaitatzis, Nikolaos ^{[1
]}

Peck, Gerrard ^{[1
]}

Coates, Nigel J. ^{[1
]}

Moso, Steven J. ^{[1
]}

Radzom, Markus ^{[1
]}

Foster, Teresa A. ^{[1
]}

Sheridan, Rose M. ^{[1
]}

Gregory, Matthew A. ^{[1
]}

Roe, S. Mark ^{[2
]}

Prodromou, Chrisostomos ^{[2
]}

Pearl, Laurence ^{[2
]}

Boyd, Susan M. ^{[3
]}

Wilkinson, Barrie ^{[1
]}

Martin, Christine J. ^{[1
]}

机构：

[1] Biot Technol Ltd, Saffron Walden CB10 1XL, Essex, England

[2] Inst Canc Res, Chester Beatty Labs, Sect Struct Biol, London SW3 6JB, England

[3] CompChem Solut, St Johns Innovat Ctr, Cambridge CB4 0WS, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 18期

关键词：

D O I：

10.1021/jm8006068

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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

引用

页码：5494 / 5497

页数：4

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