Issue 8, 2016

Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and 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-pyrimidine 25 was also shown to have high potency against the CDK9 enzyme (3 nM).

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

Associated articles

Supplementary files

Article information

Article type
Research Article
Submitted
18 Mar 2016
Accepted
07 Jun 2016
First published
13 Jun 2016
This article is Open Access
Creative Commons BY license

Med. Chem. Commun., 2016,7, 1580-1586

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

C. S. Rye, N. E. A. Chessum, S. Lamont, K. G. Pike, P. Faulder, J. Demeritt, P. Kemmitt, J. Tucker, L. Zani, M. D. Cheeseman, R. Isaac, L. Goodwin, J. Boros, F. Raynaud, A. Hayes, A. T. Henley, E. de Billy, C. J. Lynch, S. Y. Sharp, R. te Poele, L. O. Fee, K. M. Foote, S. Green, P. Workman and K. Jones, Med. Chem. Commun., 2016, 7, 1580 DOI: 10.1039/C6MD00159A

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