Project Description
Heat shock protein 90 (Hsp90) – phase II candidate
Brough et al., J. Med. Chem. 2008
Brough et al., Inhibitors of Molecular Chaperones as Therapeutic Agents, Ch. 8, 2013
Eccles et al., Cancer Res. 2008
A combination of fragment, virtual and medium-throughput screening identified resorcinol pyrazole hit CCT-018159, which underwent structure-guided optimisation to obtain NVP-AUY922/ VER-52296. It was demonstrated that NVP-AUY922 has good pharmacokinetic properties, is efficacious, and is well tolerated, when administered as a single agent once-weekly in mouse xenograft models.
X-ray crystal structures of compounds bound to the ATP binding site of the N-terminal domain of human Hsp90R (PDB code NVP-AUY922/ Hsp90R: 2VCI)
NVP-AUY922 entered Phase I clinical trials in 2007, where it was administered by intravenous infusion in a once-weekly schedule. The Phase I data built confidence in moving the compound into global Phase II trials. In a study where the pharmacokinetic and pharmacodynamic relationship was evaluated in 36 patients, a dose-dependent induction of Hsp70 was observed in patient-derived PBMCs and the up-regulation observed at 40 mg/m2 exceeded that observed in BT474 tumour-bearing mice. Doses from 2 to 80 mg/m2 have been evaluated in a number of Phase I trials and the recommended Phase II dose was set at 70 mg/m2. NVP-AUY922 achieved clinical Proof of Concept (PoC) in April 2011.