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

Brough, P. A. et al. (2009) 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. Journal of Medicinal Chemistry, 52(15), pp. 4794-4809. (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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Drysdale, Professor Martin
• Authors: Brough, P. A., Barril, X., Borgognoni, J., Chene, P., Davies, N. G. M., Davis, B., Drysdale, M. J., Dymock, B., Eccles, S. A., Garcia-Echeverria, C., Fromont, C., Hayes, A., Hubbard, R. E., Jordan, A. M., Jensen, M. R., Massey, A., Merrett, A., Padfield, A., Parsons, R., Radimerski, T., Raynaud, F. I., Robertson, A., Roughley, S. D., Schoepfer, J., Simmonite, H., Sharp, S. Y., Surgenor, A., Valenti, M., Walls, S., Webb, P., Wood, M., Workman, P., and Wright, L.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Medicinal Chemistry
• ISSN: 0022-2623
• Published Online: 17 July 2009