Preclinical Studies to Develop an Eya2 Tyr Phosphatase Inhibitor as a Novel Medulloblastoma Therapeutic

Medulloblastoma (MB) is the most common malignant brain tumor in children. For decades, there have not been significant advances in the treatment for MB, which still includes surgery, radiation and chemotherapy. Unfortunately, these treatments can cause severe side effects, including lifelong cognitive deficiencies, endocrine dysfunction, neurological defects, emotional and social

problems, and secondary tumors. Such treatment-associated toxicities are particularly severe in children, as their brains are still growing. The most aggressive and fatal MB have high levels of the known oncogene MYC and are highly dependent on MYC for growth and progression. MYC is well established as a critical driver of many types of cancer, but as a transcription factor, it has

proven to be very difficult to target therapeutically. We have shown that MYC expression and protein stability in MB are regulated by EYA2 through its unique tyrosine phosphatase (Tyr Ptase) activity. We identified a class of potent and selective small-molecule allosteric EYA2 Tyr Ptase inhibitors and have shown that a representative compound selectively reduces MYC levels and

inhibits MB cell line growth at low to sub micromolar concentrations, efficiently crosses the blood brain barrier via multiple routes of administration and inhibits MB growth in an intracranial mouse model when delivered by oral gavage. We improved the activity/selectivity and drug-like properties of the initial compound through comprehensive medicinal chemistry and have a lead

compound, SD3-146, with favorable CNS PK properties in preliminary analyses. In this Phase I STTR project we will test the hypothesis that it is feasible to develop SD3-146 into a highly efficacious and less toxic therapeutic to inhibit MYC, and thus MYC-MB growth. The first Aim is to optimize and scale up synthesis of SD3-146 and more thoroughly evaluate drug

metabolism and pharmacokinetics (DMPK) properties and potential toxicities, so as to determine the optimal dosage and timing for delivery in vivo. The second Aim is to verify its on-target effect (pharmacodynamics, PD) and efficacy in mouse MB models. With successful completion of these aims, we expect to have sufficient data to inform a GO/NO GO decision to take our lead compound

through an STTR Phase II project for further pre-clinical development. Because EYA2 has been shown to regulate MYC levels in other cancers, including breast cancer and glioblastoma, the drug we develop may have broad applicability for treating several other difficult-to-treat cancers. Thus, the proposed research could set the stage for targeting the “undruggable” super-controller

MYC, through EYA2, in multiple tumor types.