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)
Hsp90 oral backup pre-clinical candidate
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. Read more
