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Small molecule inhibitors block Gas6-inducible TAM activation and tumorigenicity
Stanley G Kimani1, Sushil Kumar1, Nitu Bansal2
1Rutgers University, New Jersey Medical School, Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, 205 South Orange Ave, Newark, NJ 07103, USA.
Abstract:
TAM receptors (Tyro-3, Axl, and Mertk) are a family of three homologous type I receptor tyrosine kinases that are implicated in several human malignancies. Overexpression of TAMs and their major ligand Growth arrest-specific factor 6 (Gas6) is associated with more aggressive staging of cancers, poorer predicted patient survival, acquired drug resistance and metastasis. Here we describe small molecule inhibitors (RU-301 and RU-302) that target the extracellular domain of Axl at the interface of the Ig-1 ectodomain of Axl and the Lg-1 of Gas6. These inhibitors effectively block Gas6-inducible Axl receptor activation with low micromolar IC50s in cell-based reporter assays, inhibit Gas6-inducible motility in Axl-expressing cell lines, and suppress H1299 lung cancer tumor growth in a mouse xenograft NOD-SCIDγ model. Furthermore, using homology models and biochemical verifications, we show that RU301 and 302 also inhibit Gas6 inducible activation of Mertk and Tyro3 suggesting they can act as pan-TAM inhibitors that block the interface between the TAM Ig1 ectodomain and the Gas6 Lg domain. Together, these observations establish that small molecules that bind to the interface between TAM Ig1 domain and Gas6 Lg1 domain can inhibit TAM activation, and support the further development of small molecule Gas6-TAM interaction inhibitors as a novel class of cancer therapeutics.
Insights
New small molecules RU-301 and RU-302 inhibit TAM receptor tyrosine kinases (Tyro-3, Axl, Mertk) and their ligand Gas6. These inhibitors show potential for novel cancer therapeutics by blocking key interactions in aggressive cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- TAM receptors (Tyro-3, Axl, Mertk) are tyrosine kinases implicated in human cancers.
- Overexpression of TAMs and Gas6 correlates with aggressive cancer staging, poor survival, drug resistance, and metastasis.
Purpose of the Study:
- To develop small molecule inhibitors targeting the Axl receptor tyrosine kinase.
- To investigate the potential of these inhibitors as pan-TAM inhibitors for cancer therapy.
Main Methods:
- Development of small molecule inhibitors (RU-301, RU-302) targeting the Axl extracellular domain.
- Cell-based reporter assays to measure Gas6-inducible Axl activation.
- Inhibition of cell motility assays in Axl-expressing cell lines.
- Mouse xenograft model (H1299 lung cancer) to assess tumor growth suppression.
- Homology modeling and biochemical verification to assess pan-TAM inhibition.
Main Results:
- RU-301 and RU-302 effectively block Gas6-inducible Axl activation with low micromolar IC50s.
- Inhibitors suppressed Gas6-induced motility in Axl-expressing cells.
- RU-301 and RU-302 suppressed H1299 lung cancer tumor growth in vivo.
- RU-301 and RU-302 demonstrated inhibition of Mertk and Tyro3, acting as pan-TAM inhibitors.
Conclusions:
- Small molecules binding the Gas6-TAM interface can inhibit TAM activation.
- RU-301 and RU-302 represent a novel class of pan-TAM inhibitors.
- These findings support the development of Gas6-TAM interaction inhibitors as a new cancer therapeutic strategy.
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