Hsp90 oral backup pre-clinical candidate
Hits from two separate screening routes were combined into a new chemical series, delivering an orally dosed Hsp90 inhibitor that caused tumour regression — the oral follow-on to the intravenous phase II candidate.
The Challenge
NVP-AUY922 established that Hsp90 inhibition could be delivered and tolerated in the clinic, but it required intravenous infusion on a weekly schedule. Achieving the same target engagement by mouth meant building a new chemical series rather than reformulating the existing one — and doing so with the oral exposure and tolerability to support repeat dosing.
The Science
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 polarisation (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 BT474 human breast cancer xenograft model.
X-ray crystal structures of compounds bound to the ATP binding site of the N-terminal domain of human Hsp90 (PDB: 2WI7, BEP-800 / Hsp90).
Key Takeaways
- Fragment-based and in silico screening hits combined into one novel ATP-competitive series
- Affinity of 50–100 nM for Hsp90 by fluorescence polarisation competitive binding
- Characteristic Hsp90 signature confirmed in cells — oncogenic protein depletion with Hsp72 elevation
- Tumour growth regression at well tolerated doses on oral dosing in a BT474 xenograft model
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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