2. Academic Validation
  3. Combining hit identification strategies: fragment-based and in silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone

Combining hit identification strategies: fragment-based and in silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone

  • J Med Chem. 2009 Aug 13;52(15):4794-809. doi: 10.1021/jm900357y.
Paul A Brough 1,  Xavier Barril,  Jenifer Borgognoni,  Patrick Chene,  Nicholas G M Davies,  Ben Davis,  Martin J Drysdale,  Brian Dymock,  Suzanne A Eccles,  Carlos Garcia-Echeverria,  Christophe Fromont,  Angela Hayes,  Roderick E Hubbard,  Allan M Jordan,  Michael Rugaard Jensen,  Andrew Massey,  Angela Merrett,  Antony Padfield,  Rachel Parsons,  Thomas Radimerski,  Florence I Raynaud,  Alan Robertson,  Stephen D Roughley,  Joseph Schoepfer,  Heather Simmonite,  Swee Y Sharp,  Allan Surgenor,  Melanie Valenti,  Steven Walls,  Paul Webb,  Mike Wood,  Paul Workman,  Lisa Wright
Affiliations

Affiliation

  • 1 Vernalis Ltd., Granta Park, Great Abington, Cambridge CB21 6GB, UK. p.brough@vernalis.com
PMID: 19610616 DOI: 10.1021/jm900357y
Abstract

Inhibitors of the HSP90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of Cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive HSP90 inhibitors, which were designed by combining structural elements of distinct low affinity hits generated from fragment-based and in silico screening exercises in concert with structural information from X-ray protein crystallography. Examples from this series have high affinity (IC50 = 50-100 nM) for HSP90 as measured in a fluorescence polarization (FP) competitive binding assay and are active in human Cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Several examples (34a, 34d and 34i) caused tumor growth regression at well tolerated doses when administered orally in a human BT474 human breast Cancer xenograft model.

Figures