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

共 25 条

[1] Ligand efficiency indices as guideposts for drug discovery [J].

Abad-Zapatero, C ;

Metz, JT .

DRUG DISCOVERY TODAY, 2005, 10 (07) :464-469

[2]

Bagatell R, 2004, MOL CANCER THER, V3, P1021

[3] SNX2112, a synthetic heat shock protein 90 inhibitor, has potent antitumor activity against HER kinase-dependent cancers [J].

Chandarlapaty, Sarat ;

Sawai, Ayana ;

Ye, Qing ;

Scott, Anisa ;

Silinski, Melanie ;

Huang, Ken ;

Fadden, Pat ;

Partdrige, Jeff ;

Hall, Steven ;

Steed, Paul ;

Norton, Larry ;

Rosen, Neal ;

Solit, David B. .

CLINICAL CANCER RESEARCH, 2008, 14 (01) :240-248

[4] Reaction of geldanamycin and C17-substituted analogues with glutathione: Product identifications and pharmacological implications [J].

Cysyk, RL ;

Parker, RJ ;

Barchi, JJ ;

Steeg, PS ;

Hartman, NR ;

Strong, JA .

CHEMICAL RESEARCH IN TOXICOLOGY, 2006, 19 (03) :376-381

[5] Geldanamycin leads to superoxide formation by enzymatic and non-enzymatic redox cycling - Implications for studies of hsp90 and endothelial cell nitric-oxide synthase [J].

Dikalov, S ;

Landmesser, U ;

Harrison, DG .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (28) :25480-25485

[6]

GASPAR N, 2008, ACQUIRED RESISTANCE

[7] Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90 [J].

Ge, Jie ;

Normant, Emmanuel ;

Porter, James R. ;

Ali, Janid A. ;

Dembski, Marlene S. ;

Gao, Yun ;

Georges, Asimina T. ;

Grenier, Louis ;

Pak, Roger H. ;

Patterson, Jon ;

Sydor, Jens R. ;

Tibbitts, Thomas T. ;

Tong, Jeffrey K. ;

Adams, Julian ;

Palombella, Vito J. .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (15) :4606-4615

[8] A biochemical rationale for the anticancer effects of Hsp90 inhibitors: Slow, tight binding inhibition by geldanamycin and its analogues [J].

Gooljarsingh, Lata T. ;

Fernandes, Christine ;

Yan, Kang ;

Zhang, Hong ;

Grooms, Michael ;

Johanson, Kyung ;

Sinnamon, Robert H. ;

Kirkpatrick, Robert B. ;

Kerrigan, John ;

Lewis, Tia ;

Arnone, Marc ;

King, Alastair J. ;

Lai, Zhihong ;

Copeland, Robert A. ;

Tummino, Peter J. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (20) :7625-7630

[9] The hallmarks of cancer [J].

Hanahan, D ;

Weinberg, RA .

CELL, 2000, 100 (01) :57-70

[10] Crystal structure and molecular modeling of 17-DMAG in complex with human Hsp90 [J].

Jez, JM ;

Chen, JCH ;

Rastelli, G ;

Stroud, RM ;

Santi, DV .

CHEMISTRY & BIOLOGY, 2003, 10 (04) :361-368

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