Hsp90 oral backup pre-clinical candidate
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.