Discovery of 4, 6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK912. Issue 8 (20th June 2016)

• Record Type: Journal Article
• Authors: Rye, Carl S.; Chessum, Nicola E. A.; Lamont, Scott; Pike, Kurt G.; Faulder, Paul; Demeritt, Julie; Kemmitt, Paul; Tucker, Julie; Zani, Lorenzo; Cheeseman, Matthew D.; Isaac, Rosie; Goodwin, Louise; Boros, Joanna; Raynaud, Florence; Hayes, Angela; Henley, Alan T.; de Billy, Emmanuel; Lynch, Christopher J.; Sharp, Swee Y.; te Poele, Robert; Fee, Lisa O'; Foote, Kevin M.; Green, Stephen; Workman, Paul; Jones, Keith
• Is Part Of: MedChemComm. Volume 7:Issue 8(2016:Aug.)
• Page Start: 1580
• Page End: 1586
• Publication Date: 2016-06-20
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19
• DOI: 10.1039/c6md00159a
• Languages: English
• ISSNs: 2040-2503

Abstract

Abstract : A series of 4, 6-disubstituted pyrimidines from a phenotypic screen targeting the HSF1 pathway are also potent inhibitors of CDK9. Abstract : 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-pyrimidine25 was also shown to have high potency against the CDK9 enzyme (3 nM).