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Discovery of Novel TYRO3/MERTK Dual Inhibitors
Deyu Kong1, Jichen Zhao1, Daowei Huang1
1Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Abstract:
The TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases has roles in oncogenesis and innate immunity, but the relative importance of the family members can differ in different contexts and between tumor types or individual tumors. Dual TYRO3 and MERTK inhibition may be advantageous for treatment of diseases or in tumors that are dependent on their coordinated action. Here, we report the discovery of the first potent dual TYRO3/MERTK inhibitor, UNC9435 (44). UNC9435 has 46-fold and 120-fold selectivity of MERTK over AXL and FLT3, respectively, and selectively against a panel of 30 other kinases. TYRO3 and MERTK inhibitory activities were confirmed by NanoBRET assays in HEK293 cells, with <0.51 nM EC50 values for both enzymes and >3000-fold selectivity over AXL. UNC9435 also inhibited TYRO3, MERTK, and downstream oncogenic signaling in cancer cells and reduced colony formation in non-small cell lung cancer cultures, indicating its potential as a novel cancer therapeutic.
Insights
Researchers discovered UNC9435, the first potent dual inhibitor targeting TYRO3 and MERTK receptor tyrosine kinases. This new compound shows promise for treating cancers reliant on these specific oncogenic pathways.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- The TAM receptor tyrosine kinase family (TYRO3, AXL, MERTK) plays critical roles in oncogenesis and innate immunity.
- Differential expression and function of TAM family members necessitate context-specific therapeutic strategies.
- Targeting coordinated TYRO3 and MERTK action may offer therapeutic advantages in certain diseases and tumors.
Purpose of the Study:
- To discover and characterize the first potent dual inhibitor of TYRO3 and MERTK.
- To evaluate the selectivity and efficacy of the novel inhibitor against cancer-relevant targets and pathways.
Main Methods:
- Discovery of UNC9435, a novel small molecule inhibitor.
- Biochemical assays (NanoBRET) to determine enzyme inhibition and selectivity.
- Cell-based assays to assess inhibition of downstream signaling and cellular effects (colony formation).
Main Results:
- UNC9435 is the first identified potent dual inhibitor of TYRO3 and MERTK.
- The compound exhibits high selectivity for MERTK over AXL and FLT3, and broad selectivity against other kinases.
- UNC9435 effectively inhibits TYRO3 and MERTK signaling in cancer cells and reduces non-small cell lung cancer colony formation.
Conclusions:
- UNC9435 represents a promising novel therapeutic candidate for cancers dependent on TYRO3 and MERTK signaling.
- The dual inhibition strategy targeting TYRO3 and MERTK warrants further investigation for cancer treatment.
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