title: Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen.
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.
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Cheeseman
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Nicola E A
authors.initials: NE
authors.lastname: Chessum
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Carl S
authors.initials: CS
authors.lastname: Rye
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: A Elisa
authors.initials: AE
authors.lastname: Pasqua
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Tucker
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Birgit
authors.identifier: 0000-0002-1896-3708
authors.initials: B
authors.lastname: Wilding
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Lindsay E
authors.initials: LE
authors.lastname: Evans
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Susan
authors.initials: S
authors.lastname: Lepri
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Meirion
authors.initials: M
authors.lastname: Richards
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Swee Y
authors.initials: SY
authors.lastname: Sharp
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.|Division of Structural Biology at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Salyha
authors.initials: S
authors.lastname: Ali
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Rowlands
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Lisa
authors.initials: L
authors.lastname: O'Fee
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Asadh
authors.initials: A
authors.lastname: Miah
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Angela
authors.initials: A
authors.lastname: Hayes
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Henley
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Marissa
authors.initials: M
authors.lastname: Powers
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Te Poele
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: De Billy
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Loredana
authors.initials: L
authors.lastname: Pellegrino
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Florence
authors.initials: F
authors.lastname: Raynaud
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Burke
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.|Division of Structural Biology at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Rob L M
authors.initials: RL
authors.lastname: van Montfort
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SW7 3RP, United Kingdom.
authors.forename: Keith
authors.identifier: 0000-0002-9440-4094
authors.initials: K
authors.lastname: Jones
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D001682:Biological Availability; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D002352:Carrier Proteins / Q000737:chemistry*; D004268:DNA-Binding Proteins / Q000737:chemistry*; D049308:Dioxygenases; D055808:Drug Discovery; D000076249:Heat Shock Transcription Factors; D008024:Ligands; D009687:Nuclear Proteins / Q000737:chemistry*; D066244:Proton Magnetic Resonance Spectroscopy; D011804:Quinolines / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D014157:Transcription Factors / Q000737:chemistry*
chemical_list: D000577:Amides; C000621651:CCT251236; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D008024:Ligands; D009687:Nuclear Proteins; D011804:Quinolines; D014157:Transcription Factors; D049308:Dioxygenases; C105340:PIR protein, human