期刊
MEDCHEMCOMM
卷 7, 期 8, 页码 1580-1586出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c6md00159a
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资金
- Cancer Research UK [C309/A8274, C309/A11566]
- Institute of Cancer Research
- Cancer Research UK [11566] Funding Source: researchfish
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 mu M). 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).
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