Hsp90 phase II candidate
Three screening approaches converged on a single hit series, optimised into NVP-AUY922 — the Vernalis compound that went furthest, reaching clinical proof of concept.
The Challenge
Hsp90 is a molecular chaperone that many oncogenic client proteins depend on to fold and function, making it a route to disabling several cancer drivers at once. Realising that opportunity requires a starting point in a well-studied ATP binding site, and a compound with the pharmacokinetics and tolerability to sustain repeat dosing in the clinic.
The Science
A combination of fragment, virtual and medium-throughput screening identified the resorcinol pyrazole hit CCT-018159, which underwent structure-guided optimisation to obtain NVP-AUY922 / VER-52296.
NVP-AUY922 was shown to have good pharmacokinetic properties, to be efficacious, and to be well tolerated when administered as a single agent once weekly in mouse xenograft models.
NVP-AUY922 entered phase I clinical trials in 2007, administered by intravenous infusion on a once-weekly schedule. The phase I data built confidence in moving the compound into global phase II trials. In a study evaluating the pharmacokinetic and pharmacodynamic relationship 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 were evaluated across 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 in April 2011.
X-ray crystal structures of compounds bound to the ATP binding site of the N-terminal domain of human Hsp90 (PDB: 2VCI).
Key Takeaways
- Fragment, virtual and medium-throughput screening converged on one hit series
- Translational PK/PD confirmed in 36 patients — Hsp70 induction exceeded the mouse benchmark
- Recommended phase II dose established at 70 mg/m2
- Clinical proof of concept achieved April 2011
Service Areas
Work with us
Vernalis has collaborated with a wide range of partners to enable some of the most challenging therapeutic targets. Present and past collaborators include Servier, Pierre Fabre, Genentech and Lundbeck. Vernalis can support programs with DEL and fragment-based technologies through to establishing full drug discovery programmes for our partners.
Our track record is built on innovation and success in enabling drug discovery and identifying clinical candidates for a wide variety of therapeutic targets.
Research Director and Joint Site Lead
James Murray PhD
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