Prev. Article Next Article Table of Contents

Brief Article

Molecular Characterization of Macbecin as an Hsp90 Inhibitor^#

Supporting Info

Christine J. Martin*^†, Sabine Gaisser^†, Iain R. Challis^†, Isabelle Carletti^†, Barrie Wilkinson^†, Matthew Gregory^†, Chrisostomos Prodromou^‡, S. Mark Roe^‡, Laurence H. Pearl^‡, Susan M. Boyd^§ and Ming-Qiang Zhang^†

Biotica Technology Limited, Chesterford Research Park, Essex CB10 1XL, U.K., Section of Structural Biology, Chester Beatty Laboratories, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, U.K., and CompChem Solutions, St. John’s Innovation Centre, Cowley Road, Cambridge CB4 0WS, U.K.

J. Med. Chem., 2008, 51 (9), pp 2853–2857

DOI: 10.1021/jm701558c

Publication Date (Web): March 22, 2008

PDB code of crystal structure of macbecin I bound to Hsp90: 2VLS.

* To whom correspondence should be addressed. Phone: +44 1799 532927 . Fax: +44 1799 532921. E-mail: christine.martin@biotica.com.

†

Biotica Technology Limited.

‡

Institute of Cancer Research.

CompChem Solutions.

Abstract

Macbecin compares favorably to geldanamycin as an Hsp90 inhibitor, being more soluble, stable, more potently inhibiting ATPase activity (IC₅₀ = 2 µM) and binding with higher affinity (K_d = 0.24 µM). Structural studies reveal significant differences in their Hsp90 binding characteristics, and macbecin-induced tumor cell growth inhibition is accompanied by characteristic degradation of Hsp90 client proteins. Macbecin significantly reduced tumor growth rates (minimum T/C: 32%) in a DU145 murine xenograft. Macbecin thus represents an attractive lead for further optimization.

View: Full Text HTML | Hi-Res PDF | PDF w/ Links

Tools

SciFinder Links

Accession Codes

History

Published In Issue May 08, 2008
Article ASAPMarch 22, 2008
Received: December 13, 2007

Recommend & Share

Related Content

Discovery of Benzisoxazoles as Potent Inhibitors of Chaperone Heat Shock Protein 90Journal of Medicinal Chemistry
- Discovery of Benzisoxazoles as Potent Inhibitors of Chaperone Heat Shock Protein 90
  Ariamala Gopalsamy, Mengxiao Shi, Jennifer Golas, Erik Vogan, Jaison Jacob, Mark Johnson, Frederick Lee, Ramaswamy Nilakantan, Roseann Petersen, Kristin Svenson, Rajiv Chopra, May S. Tam, Yingxia Wen, John Ellingboe, Kim Arndt and Frank Boschelli
  Journal of Medicinal Chemistry 2008 51 (3), pp 373–375
  Abstract: Heat shock protein 90 (Hsp90) is a molecular chaperone that is responsible for activating many signaling proteins and is a promising target in tumor biology. We have identified small-molecule benzisoxazole derivatives as Hsp90 inhibitors. Crystallographic ...
  Abstract | Full Text HTML | PDF w/ Links | Hi-Res PDF
Novel, Potent Small-Molecule Inhibitors of the Molecular Chaperone Hsp90 Discovered through Structure-Based DesignJournal of Medicinal Chemistry
- Novel, Potent Small-Molecule Inhibitors of the Molecular Chaperone Hsp90 Discovered through Structure-Based Design
  Brian W. Dymock, Xavier Barril, Paul A. Brough, Julie E. Cansfield, Andrew Massey, Edward McDonald, Roderick E. Hubbard, Allan Surgenor, Stephen D. Roughley, Paul Webb, Paul Workman, Lisa Wright, and Martin J. Drysdale
  Journal of Medicinal Chemistry 2005 48 (13), pp 4212–4215
  Abstract: The crystal structure of a previously reported screening hit 1 (CCT018159) bound to the N terminal domain of molecular chaperone Hsp90 has been used to design 5-amide analogues. These exhibit enhanced potency against the target in binding and functional ...
  Abstract | Full Text HTML | Hi-Res PDF
4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of CancerJournal of Medicinal Chemistry
- 4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer
  Paul A. Brough, Wynne Aherne, Xavier Barril, Jenifer Borgognoni, Kathy Boxall, Julie E. Cansfield, Kwai-Ming J. Cheung, Ian Collins, Nicholas G. M. Davies, Martin J. Drysdale, Brian Dymock, Suzanne A. Eccles, Harry Finch, Alexandra Fink, Angela Hayes, Robert Howes, Roderick E. Hubbard, Karen James, Allan M. Jordan, Andrea Lockie, Vanessa Martins, Andrew Massey, Thomas P. Matthews, Edward McDonald, Christopher J. Northfield, Laurence H. Pearl, Chrisostomos Prodromou, Stuart Ray, Florence I. Raynaud, Stephen D. Roughley, Swee Y. Sharp, Allan Surgenor, D. Lee Walmsley, Paul Webb, Mike Wood, Paul Workman and Lisa Wright
  Journal of Medicinal Chemistry 2008 51 (2), pp 196–218
  Abstract: Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure−activity relationships and pharmacokinetics of potent small-...
  Abstract | Full Text HTML | PDF w/ Links | Hi-Res PDF

Brief Article

Molecular Characterization of Macbecin as an Hsp90 Inhibitor^#