Abstract 2831: Development of selective GRP94 inhibitors for the treatment of cancer

Glucose Regulated Protein 94 (Grp94) is an Hsp90 paralog localized in the lumen of the endoplasmic reticulum (ER) of higher eukaryotes. While the mechanisms associated with Grp94-pathogenic expression are still actively studied, the focus thus far of most cancer related studies has been primarily on the immunogenic activity of Grp94/peptide complexes and the involvement of this protein in the secretion of IGF-I and IGF-II and the regulation of Toll-like receptors and integrins. This status quo has recently changed when work from our lab has shown that in certain breast cancers the maintenance of a high density HER2 species at the plasma membrane and its associated aberrant signaling also requires Grp94, rendering these tumors highly sensitive to Grp94 inhibition. The discovery of selective and potent Grp94 inhibitors has been hindered due to the high similarity of the ATP-binding regulatory pocket of the Hsp90 paralogs. However, recent work from our lab has shown that this apparent roadblock can be overcome by using library screening and structural and computational analysis to discover purine-based molecules that show 100-fold selectivity for the Grp94 isoform. Herein, we detail for the first time the structure activity relationship of the selective purine derived Grp94 molecules. This work provides insights on how to overcome the high structural similarity of Hsp90s in the ligand binding pocket, and also reports selective and therapeutically relevant Grp94 inhibitors based on a purine scaffold. These initial inhibitors have potent activity against cancer cells providing an important platform for the development of Grp94 inhibitors with drug-like features and potential for clinical translation. Citation Format: Stefan O. Ochiana, Tony Taldone, Hardik J. Patel, Pallav Patel, Yan Pengrong, Weilin Sun, Anna Rodina, Smit Shah, Daniel T. Gewirth, Gabriela Chiosis. Development of selective GRP94 inhibitors for the treatment of cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2831. doi:10.1158/1538-7445.AM2015-2831