Structure-Based Design of Grp94-Selective Inhibitors

Abstract

Heat shock protein 90 KDa (Hsp90) belongs to family of proteins called molecular chaperone that are associated with protein folding and maturation. Hsp90 clients play a critical role in the pathogenesis of diseases such as cancer, neurodegeneration and infection. Currently, clinical trials are underway for various Hsp90 inhibitors, however, all of these inhibitors exhibit paninhibition of all four Hsp90 isoforms, which could be the cause of side effects observed with these inhibitors, including, hepatotoxicity, cardiotoxicity, and renal toxicity. Hence, the development of isoform selective Hsp90 inhibitor is needed to delineate the role each Hsp90 isoform plays towards the pathogenesis of these toxicities. One such isoform is the ER residing glucose regulated protein (Grp94), which is important for cellular communication and adhesion. Co-crystallization studies of radamide, an Hsp90 pan-inhibitor developed in our lab established that there exists a unique hydrophobic pocket found only in Grp94. To probe this pocket, two approaches have been investigated; 1) des-quinone analogs of radamide and 2) employing cis-amide isosteres. The co-crystal structure of cis-amide isostere compound BnIm bound to Gp94 and Hsp90 led to the discovery of a novel pocket in Grp94 due to ligand induced conformational change. This pocket has been probed by the modification of SNX 2112, a pan-inhibitor of Hsp90 that is currently undergoing clinical evaluation. These modifications have resulted in the identification of ACO1, which exhibits good potency and high selectivity towards Grp94. Rationale for the design of ACO analogs is discussed alongside their inhibition activities.