Pilot Studies of NN-01-195, a New Tumor-Targeted AURKA Inhibitor - Project Summary/Abstract A critical barrier limiting the use of some protein-targeted therapies is the inability to concentrate them in solid tumors at sufficient levels to achieve therapeutic benefit without simultaneously inducing untenable degrees of toxicity in normal tissues. One promising approach has been to develop drug conjugates, in which a compound with desirable anti-cancer activities is fused to a second compound that selectively binds to a target that is highly enriched in tumors. We have previously had success in using a drug conjugate containing an HSP90-binding moiety fused to SN38, the active metabolite of irinotecan, showing this achieved greater efficacy due to specific retention in tumors in vivo; this compound is now in clinical trials. We have now extended this approach to create a new chimeric compound fusing an HSP90 inhibitor derived from the clinical compound SNX-2112 to an inhibitor of Aurora-A kinase (AURKA), TAS-119. AURKA is a well-validated cancer target that has elevated activity in many solid tumors, causing mitotic abnormalities, and promoting proliferative, anti-apoptotic, and invasion signaling. Numerous AURKA inhibitors have been tested clinically, but dose limited toxicities have restricted their broad use. In preliminary studies, we have shown the new chimeric compound, NN-01-195, retains binding activity for both HSP90 and AURKA. NN-01-195 also has in vitro potency in reducing viability, and causes G2/M cell cycle arrest, comparable to its parental AURKA inhibitor, TAS-119. Reverse phase protein array (RPPA) analysis also suggests similar signaling responses to NN-01-195 and TAS-119 Preliminary ADME/pharmacokinetic analysis demonstrated a favorable profile for metabolism in liver microsomes (T1/2 = 46.7 minutes), and a reasonable stability in plasma with a T1/2 of about 4-5 hours. The goal of this proposal is to gain essential pilot and feasibility studies that establish the mechanism of action of NN-01-195 and begin to define the in vivo accumulation and efficacy of this drug. In Aim 1, we will further clarify the mode of action of NN-01-195. For this, we will treat cells with NN-01-195, SNX-2112, TAS-119, or vehicle, and perform RNA sequencing, and profile downstream signaling events and transcriptional profile. This will establish whether NN-01-195 treatment induces changes similar to TAS119 (preferred hypothesis, based on preliminary data), to SNX-2112, to combined 1:1 application of TAS-119 and SNX-2112, or instead has a neomorphic activity, closely resembling neither parent compound. We will also directly compare the ability of NN-01-195 and TAS119 to induce G2/M arrest and AURKA inhibition. Finally, we will begin to evaluate two recently synthesized NN-01-195 analogs for activity. In Aim 2, we will establish the NN-01-195 maximum tolerated dose (MTD) and tumor retention. We will also gauge NN-01-195 efficacy in inhibiting AURKA cancer xenografts, benchmarking to TAS-119 and SNX-2112.
