Document Report Card

ID: ALA3861941

Journal: Medchemcomm

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

Authors: Rye CS, Chessum NE, Lamont S, Pike KG, Faulder P, Demeritt J, Kemmitt P, Tucker J, Zani L, Cheeseman MD, Isaac R, Goodwin L, Boros J, Raynaud F, Hayes A, Henley AT, de Billy E, Lynch CJ, Sharp SY, Te Poele R, Fee LO, Foote KM, Green S, Workman P, Jones K.

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).

CiteXplore: 27746890

DOI: 10.1039/C6MD00159A