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

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 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.