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

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

  • J Med Chem. 2017 Jan 12;60(1):180-201. doi: 10.1021/acs.jmedchem.6b01055.
Matthew D Cheeseman 1,  Nicola E A Chessum 1,  Carl S Rye 1,  A Elisa Pasqua 1,  Michael J Tucker 1,  Birgit Wilding 1,  Lindsay E Evans 1,  Susan Lepri 1,  Meirion Richards 1,  Swee Y Sharp 1,  Salyha Ali 1 2,  Martin Rowlands 1,  Lisa O'Fee 1,  Asadh Miah 1,  Angela Hayes 1,  Alan T Henley 1,  Marissa Powers 1,  Robert Te Poele 1,  Emmanuel De Billy 1,  Loredana Pellegrino 1,  Florence Raynaud 1,  Rosemary Burke 1,  Rob L M van Montfort 1 2,  Suzanne A Eccles 1,  Paul Workman 1,  Keith Jones 1
Affiliations

Affiliations

  • 1 Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
  • 2 Division of Structural Biology at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
PMID: 28004573 DOI: 10.1021/acs.jmedchem.6b01055
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-101026
    98.82%, PROTAC Ligand
    HSP