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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 ?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).

SUBMITTER: Rye CS

PROVIDER: S-EPMC5048338 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Rye Carl S CS Chessum Nicola E A NE Lamont Scott S Pike Kurt G KG Faulder Paul P Demeritt Julie J Kemmitt Paul P Tucker Julie J Zani Lorenzo L Cheeseman Matthew D MD Isaac Rosie R Goodwin Louise L Boros Joanna J Raynaud Florence F Hayes Angela A Henley Alan T AT de Billy Emmanuel E Lynch Christopher J CJ Sharp Swee Y SY Te Poele Robert R Fee Lisa O' LO Foote Kevin M KM Green Stephen S Workman Paul P Jones Keith K

MedChemComm 20160613 8

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 le ...[more]

PMID: 27746890

Dataset Information

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

Publications

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

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