Brough et al., J. Med. Chem. 2009

Massey et al., Mol. Cancer Ther. 2010

Inhibitors of the Hsp90 molecular chaperone are potential therapeutic agents for the treatment of cancer. Novel 2-aminothieno[2,3-d]pyrimidine, ATP competitive, Hsp90 inhibitors were synthesised, designed by combining structural elements of distinct low affinity hits generated from fragment-based and in silico screening exercises, in concert with structural information from X-ray protein crystallography. Examples from this series have high affinity (IC₅₀ = 50–100 nM) for Hsp90 as measured in a fluorescence polarization (FP) competitive binding assay, are active in human cancer cell lines where they inhibit cell proliferation, and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Several examples caused tumour growth regression at well tolerated doses when administered orally in a human BT474 human breast cancer xenograft model.

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X-ray crystal structures of compounds bound to the ATP binding site of the N-terminal domain of human Hsp90R (PDB code BEP-800/ Hsp90: 2WI7)