Discovery of 4,6-disubstituted pyrimidines as potent inhibitors of the heat shock factor 1 (HSF1) stress pathway and CDK9.
de Billy, E
Te Poele, R
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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 (<b>1</b>) based on a 4,6-pyrimidine scaffold (2.00 μM). Optimisation of cellular SAR led to an inhibitor with improved potency (<b>25</b>, 15 nM) in the HSF1 phenotypic assay. The 4,6-pyrimidine <b>25</b> was also shown to have high potency against the CDK9 enzyme (3 nM).
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Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 3
Sarcoma and Melanoma Surgery
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MedChemComm, 2016, 7 (8), pp. 1580 - 1586