# Novel TYRO3 inhibitors for treatment of cancer

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $306,926

## Abstract

TYRO3 is a member of the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases. All three
family members are aberrantly expressed in cancer cells, where they function to promote cell survival, mediate
resistance to a variety of cytotoxic chemotherapies and molecularly-targeted agents and have additional roles in
macrophages and other innate immune cells where they function to suppress anti-tumor immunity, leading to
enhanced tumor growth and metastasis. These and other data implicate the TAM kinases as potential
therapeutic targets in a wide variety of human tumors. Moreover, because of the oncogenic roles for TAM kinases
in both tumor and immune cells, inhibitors are expected to provide anti-tumor action mediated by both direct
tumor cell killing and modulation of the innate immune response. While the TAM kinases have overlapping
functions, they also play unique roles in some contexts. Specifically, our preliminary data suggest that
suppression of anti-tumor immunity is particularly dependent on TYRO3.
 Here, we propose to utilize a well-established and productive team of researchers along with
computational-aided drug design and enzymatic, cell-based and pharmacodynamic assays to develop novel,
potent, and selective TYRO3 inhibitors and validate their biochemical and functional activities in TYRO3-
dependent tumor xenograft models and immune-competent syngeneic cancer models. TYRO3 can localize to
the nucleus and inhibition of nuclear localization induced apoptosis in colon cancer cells, suggesting non-
canonical oncogenic functions for TYRO3 which might not be effectively targeted by kinase inhibition alone.
Thus, both traditional small molecule kinase inhibitors and proteolysis-targeting chimeric (PROTAC) degraders
that selectively target TYRO3 for ubiquitination and degradation will be developed and compared. At the
completion of this work, we expect to deliver a TYRO3-selective inhibitor suitable for advancement to GLP toxicity
studies in multiple species, sufficient preclinical validation studies to support an IND application describing this
compound, and a viable method for large-scale synthesis of the compound.

## Key facts

- **NIH application ID:** 10815535
- **Project number:** 5R01CA259077-04
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** DOUGLAS K GRAHAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $306,926
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10815535

## Citation

> US National Institutes of Health, RePORTER application 10815535, Novel TYRO3 inhibitors for treatment of cancer (5R01CA259077-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10815535. Licensed CC0.

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