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Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen

2016; American Chemical Society; Volume: 60; Issue: 1 Linguagem: Inglês

10.1021/acs.jmedchem.6b01055

1520-4804

Matthew D. Cheeseman, N. Chessum, Carl S. Rye, Elisa Pasqua, Michael Tucker, Birgit Wilding, Lindsay E. Evans, Susan Lepri, Meirion Richards, Swee Y. Sharp, Salyha Ali, Martin Rowlands, Lisa O’Fee, Asadh Miah, Angela Hayes, Alan T. Henley, Marissa Powers, Robert te Poele, Emmanuel de Billy, Loredana Pellegrino, Florence I. Raynaud, Rosemary Burke, Rob L. M. van Montfort, Suzanne A. Eccles, Paul Workman, Keith Jones,

ATP Synthase and ATPases Research

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.