Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9

Medchemcomm. 2016 Aug 1;7(8):1580-1586. doi: 10.1039/c6md00159a.

Carl S Rye ¹, Nicola E A Chessum ¹, Scott Lamont ², Kurt G Pike ², Paul Faulder ², Julie Demeritt ², Paul Kemmitt ², Julie Tucker ², Lorenzo Zani ¹, Matthew D Cheeseman ¹, Rosie Isaac ², Louise Goodwin ², Joanna Boros ², Florence Raynaud ¹, Angela Hayes ¹, Alan T Henley ¹, Emmanuel de Billy ¹, Christopher J Lynch ¹, Swee Y Sharp ¹, Robert Te Poele ¹, Lisa O' Fee ¹, Kevin M Foote ², Stephen Green ², Paul Workman ¹, Keith Jones ¹

Affiliations

1 Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London SW7 3RP , UK . Email: Paul.Workman@icr.ac.uk ; Email: Keith.Jones@icr.ac.uk.
2 AstraZeneca , Alderley Park , Macclesfield , Cheshire , SK10 4TG , UK.

PMID: 27746890 DOI: 10.1039/c6md00159a

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-pyrimidine 25 was also shown to have high potency against the CDK9 Enzyme (3 nM).

Name
Email *

	Sorry, but the email address you supplied was invalid.