Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen
Matthew D. Cheeseman(Institute of Cancer Research), N. Chessum(Institute of Cancer Research), Carl S. Rye(Institute of Cancer Research), Elisa Pasqua(Institute of Cancer Research), Michael Tucker(Institute of Cancer Research), Birgit Wilding(Institute of Cancer Research), Lindsay E. Evans(Institute of Cancer Research), Susan Lepri(Institute of Cancer Research), Meirion Richards(Institute of Cancer Research), Swee Y. Sharp(Institute of Cancer Research), Salyha Ali(Institute of Cancer Research), Martin Rowlands(Institute of Cancer Research), Lisa O’Fee(Institute of Cancer Research), Asadh Miah(Institute of Cancer Research), Angela Hayes(Institute of Cancer Research), Alan T. Henley(Institute of Cancer Research), Marissa Powers(Institute of Cancer Research), Robert te Poele(Institute of Cancer Research), Emmanuel de Billy(Institute of Cancer Research), Loredana Pellegrino(Institute of Cancer Research), Florence I. Raynaud(Institute of Cancer Research), Rosemary Burke(Institute of Cancer Research), Rob L. M. van Montfort(Institute of Cancer Research), Suzanne A. Eccles(Institute of Cancer Research), Paul Workman(Institute of Cancer Research), Keith Jones(Institute of Cancer Research)
Cited by 70Open Access
Abstract
Phenotypic screens, which focus on measuring and quantifying discrete cellular changes rather than affinity for individual recombinant proteins, have recently attracted renewed interest as an efficient strategy for drug discovery. In this article, we describe the discovery of a new chemical probe, bisamide (CCT251236), identified using an unbiased phenotypic screen to detect inhibitors of the HSF1 stress pathway. The chemical probe is orally bioavailable and displays efficacy in a human ovarian carcinoma xenograft model. By developing cell-based SAR and using chemical proteomics, we identified pirin as a high affinity molecular target, which was confirmed by SPR and crystallography.
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