Novel Hsp90 inhibitors exhibiting in vivo xenograft activity discovered using fragment-based drug discovery & structure based drug design.

5716 Inhibition of Heat Shock Protein 90 (Hsp90) results in the selective degradation of several oncogenic targets, which require the chaperone for folding. Ansamycin antibiotics demonstrate anti-proliferative activity in cancer cells and xenograft models and are currently in oncology clinical trials. Here we describe the development of a novel series of low molecular weight Hsp90 inhibitors using fragment based high-throughput x-ray crystallography. The direct binding of these compounds to Hsp90 has been demonstrated in vitro, as well as their anti-proliferative effects in a range of cancer cell lines. The compound mechanism of action has been confirmed, by the selective down-regulation of known Hsp90 client proteins and the resulting inhibition of proliferative and cell survival signalling pathways. In addition this series of compounds exhibited potent anti-tumour activity when dose against tumour bearing nude Hct116 mice. The in vivo pharmacodynamic properties of this compound series will also be described.