Abstract A211: Fragment-based drug discovery of the synthetic small molecule HSP90 inhibitor AT13387

• Published in: Molecular cancer therapeutics Vol. 8; no. 12_Supplement; p. A211
• Main Authors: Murray, Christopher W., Carr, Maria G., Chessari, Gianni, Congreve, Miles, Coyle, Joseph E., Day, Philip J., Fazal, Lynsey, Frederickson, Martyn, Graham, Brent, Lewis, Jonathan, McMenamin, Rachel, O'Brien, Alistair, Patel, Sahil, Williams, Glyn, Woodhead, Andrew J., Woolford, Alison J.
• Format: Journal Article
• Language: English
• Published: 10.12.2009
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-09-A211

Abstract Heat Shock Protein 90 (HSP90) is a member of a family of molecular chaperone proteins which directs the folding of polypeptides into functional configurations affecting stabilisation and activation. Many of these proteins are oncogenes regulating tumor cell growth, survival and apoptosis. This poster will focus on the screening and medicinal chemistry work that led to the identification of AT13387, a high affinity HSP90 inhibitor that is currently in clinical trials for the treatment of cancer. A fragment screening campaign was conducted against the N-terminal domain of HSP90 to detect very low molecular weight compounds (Molecular Weight <250 Da) that bound to the ATPase active site. The screening produced a small fragment which was co-crystallised with HSP90 and had an affinity of 790µM. Three iterations of structure-guided medicinal chemistry led to the identification of a lead compound with 0.5nM affinity for the enzyme, good cell activity and confirmed mechanism of action in cells. The fragment to lead optimisation increased affinity by over a million fold but resulted in a molecule that was only 6 heavy atoms larger than the fragment starting point. Such an efficient optimisation campaign is unprecedented in the field of fragment-based drug discovery. Subsequent lead optimisation focussed on the improvement of in vivo distribution properties via the addition of basic moieties to the lead molecule. These compounds showed encouraging in vivo pharmacology and biological profiles, and further medicinal chemistry work led to the discovery of AT13387, an inhibitor with sub-nanomolar affinity, prolonged duration of action and excellent in vivo anti-tumor efficacy. This poster represents first disclosure of the structure of AT13387 and illustrates how a fragment-based drug discovery approach can be efficiently used to discover compounds suitable for clinical testing in oncology. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A211.