NN-01-195, a novel conjugate of HSP90 and AURKA inhibitors, effectively targets solid tumors.

Aurora kinase A (AURKA) regulates cell cycle progression into and through mitosis. As overexpression of AURKA in cancer cells is common and associated with mitotic defects and aneuploidy, small molecule inhibitors of AURKA have been developed as candidate therapies for cancer. However, these have typically low activity in clinical trials, with systemic toxicities limiting dose escalation. To concentrate an AURKA inhibitor in tumors, we exploited the fact that cancer cells in solid tumors selectively express high levels of the chaperone HSP90 to counteract intratumoral stresses, providing a potential targeting moiety. We developed NN-01-195 as a novel chimeric small molecule that combines an AURKA inhibitor related to TAS-119/VIC-1911 with an HSP90-binding moiety related to SNX2112, and evaluated its function. NN-01-195 tightly binds and inhibits both AURKA and HSP90 in biochemical assays. In cancer cells, NN-01-195 causes mitotic arrest and spindle abnormalities, and a profile of signaling changes that closely resembles that of an AURKA inhibitor. ADME assessment indicates moderate metabolism in liver microsomes (T1/2 = 46.7 minutes) and sustained plasma exposure following single I.P. injection. Maximum tolerated repeated dose testing over 5 days indicates no weight loss or toxicity at 80 mg/kg. Importantly, NN-01-195 accumulates in xenografted tumors at higher levels and for longer duration than does an AURKA inhibitor. Further, in combination with an inhibitor of the G2/M checkpoint protein WEE1, NN-01-195 is more potent than VIC-1911 in limiting growth of xenograft tumors. These data support the exploration of NN-01-195 and improved analogs as promising new candidates for therapeutic evaluation.