Hsp90 is a molecular chaperone currently the focus of significant research interest as a target for small molecule anti-cancer therapeutic agents. First in class inhibitors based on the natural product geldanamycin (including 17-AAG, 17-DMAG and IPI-504) have entered Phase I/II clinical trials. These agents confer their inhibitory effect by competitive binding to an ATP binding site on the N-terminal domain of the protein. We have previously described the elaboration of the diaryl pyrazole screening hit CCT018159 to the diaryl-isoxazole inhibitor NVP-AUY922 (currently in Phase I trials) via a structure based medicinal chemistry programme. To find a back up to this compound we have applied a combination of hit ID strategies to identify a novel inhibitor series. Fragment-based screening against Hsp90 using a combination of Saturation Transfer Difference (STD), water-LOGSY and T2 relaxation filtered 1D NMR experiments identified a number of low molecular weight fragments with weak binding affinity (IC50 ca. 500 \#956;M by fluorescence polarization (FP) assay). In parallel, a virtual screening campaign against Hsp90 using an in-house catalogue of commercially available compounds and the propriety docking software rDOCK led to distinct class of more potent lead-like inhibitors (FP IC50 ca. 1 \#956;M). Using structural information from X-ray crystallography we were able to design a novel scaffold inhibitor which was rapidly evolved by SBDD to a series of potent compounds exemplified by NVP-BEP800 (FP IC50 = 56 nM; GI50 (BT474) = 53 nM). The cellular mode of action was consistent with Hsp90 inhibition as determined by down regulation of Hsp90 client proteins and up regulation of Hsp72. NVP-BEP800 displayed excellent efficacy in a number xenograft models of cancer when administered orally at well tolerated doses and dosing regimes.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4684.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009