| Title: |
Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9. |
| Authors: |
Rye, CS; Chessum, NEA; Lamont, S; Pike, KG; Faulder, P; Demeritt, J; Kemmitt, P; Tucker, J; Zani, L; Cheeseman, MD; Isaac, R; Goodwin, L; Boros, J; Raynaud, F; Hayes, A; Henley, AT; de Billy, E; Lynch, CJ; Sharp, SY; Te Poele, R; Fee, LO; Foote, KM; Green, S; Workman, P; Jones, K |
| Contributors: |
Cheeseman, Matthew; Raynaud, Florence; Hayes, Andrew; Workman, Paul; Jones, Keith |
| Publisher Information: |
ROYAL SOC CHEMISTRY |
| Publication Year: |
2016 |
| Collection: |
The Institute of Cancer Research (ICR): Publications Repository |
| Description: |
Heat shock factor 1 (HSF1) is a transcription factor that plays key roles in cancer, including providing a mechanism for cell survival under proteotoxic stress. Therefore, inhibition of the HSF1-stress pathway represents an exciting new opportunity in cancer treatment. We employed an unbiased phenotypic screen to discover inhibitors of the HSF1-stress pathway. Using this approach we identified an initial hit (1) based on a 4,6-pyrimidine scaffold (2.00 μM). Optimisation of cellular SAR led to an inhibitor with improved potency (25, 15 nM) in the HSF1 phenotypic assay. The 4,6-pyrimidine 25 was also shown to have high potency against the CDK9 enzyme (3 nM). |
| Document Type: |
article in journal/newspaper |
| File Description: |
Print-Electronic; 1586; application/octet-stream |
| Language: |
English |
| ISSN: |
2040-2511; 2040-2503 |
| Relation: |
MedChemComm, 2016, 7 (8), pp. 1580 - 1586; https://repository.icr.ac.uk/handle/internal/120 |
| DOI: |
10.1039/c6md00159a |
| Availability: |
https://doi.org/10.1039/c6md00159a; https://repository.icr.ac.uk/handle/internal/120 |
| Rights: |
https://creativecommons.org/licenses/by/4.0 |
| Accession Number: |
edsbas.968FB104 |
| Database: |
BASE |