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

> **NIH NIH R41** · SIEYAX, INC · 2024 · $399,709

## Abstract

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.

## Key facts

- **NIH application ID:** 11006371
- **Project number:** 1R41CA291231-01A1
- **Recipient organization:** SIEYAX, INC
- **Principal Investigator:** Heide L. Ford
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $399,709
- **Award type:** 1
- **Project period:** 2024-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11006371

## Citation

> US National Institutes of Health, RePORTER application 11006371, Preclinical Studies to Develop an Eya2 Tyr Phosphatase Inhibitor as a Novel Medulloblastoma Therapeutic (1R41CA291231-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/11006371. Licensed CC0.

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