| Title: |
Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen. |
| Authors: |
Cheeseman, MD; Chessum, NEA; Rye, CS; Pasqua, AE; Tucker, MJ; Wilding, B; Evans, LE; Lepri, S; Richards, M; Sharp, SY; Ali, S; Rowlands, M; O'Fee, L; Miah, A; Hayes, A; Henley, AT; Powers, M; Te Poele, R; De Billy, E; Pellegrino, L; Raynaud, F; Burke, R; van Montfort, RLM; Eccles, SA; Workman, P; Jones, K |
| Contributors: |
Cheeseman, Matthew; Chessum, Nicola; Richards, Gareth; Ali, Salyha; Powers, Marissa; Raynaud, Florence; Burke, Rosemary; Van Montfort, Robert; Workman, Paul; Jones, Keith |
| Publisher Information: |
AMER CHEMICAL SOC |
| Publication Year: |
2016 |
| Collection: |
The Institute of Cancer Research (ICR): Publications Repository |
| Subject Terms: |
Amides; Quinolines; Carrier Proteins; DNA-Binding Proteins; Nuclear Proteins; Transcription Factors; Ligands; Spectrometry; Mass; Electrospray Ionization; Administration; Oral; Biological Availability; Drug Discovery; Proton Magnetic Resonance Spectroscopy; Carbon-13 Magnetic Resonance Spectroscopy; Heat Shock Transcription Factors |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
Print-Electronic; 201; application/pdf |
| Language: |
English |
| ISSN: |
1520-4804; 0022-2623 |
| Relation: |
Journal of medicinal chemistry, 2017, 60 (1), pp. 180 - 201; https://repository.icr.ac.uk/handle/internal/320 |
| DOI: |
10.1021/acs.jmedchem.6b01055 |
| Availability: |
https://doi.org/10.1021/acs.jmedchem.6b01055; https://repository.icr.ac.uk/handle/internal/320 |
| Rights: |
https://creativecommons.org/licenses/by/4.0 |
| Accession Number: |
edsbas.950B656A |
| Database: |
BASE |