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: [email protected] ; Email: [email protected].
  • 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).