The heat shock proteins (Hsps) act as molecular chaperones. Hsp90 is an abundant protein with roles in protein folding, cell signaling, and cancer. HSP-990 is an Hsp90 inhibitor with IC50 values of 0.6, 0.8, and 8.5 nM for Hsp90α, Hsp90β, and GRP94, respectively. It inhibits the TRAP1 ATPase with an IC50 value of 320 nM and demonstrates IC50 values of >5 μM in a panel of 51 unrelated kinases. In c-Met amplified GTL-16 gastric tumor cells, HSP-990 has been shown to dissociate the Hsp90-p23 complex, depleting the client protein c-Met and inducing Hsp70. HSP-990 can inhibit proliferation of various human tumor cell lines with GI50 values of 4-40 nM. Single oral administration of 15 mg/kg of HSP-990 was shown to induce sustained downregulation of c-Met and upregulation of Hsp70 in a GTL-16 xenograft model.
