Small molecule inhibitors block Gas6-inducible TAM activation and tumorigenicity
| Autor: | Thomas W. Comollo, Stanley G. Kimani, Kamalendra Singh, Joseph R. Bertino, Sergei V. Kotenko, Vladyslav Kholodovych, Youyi Peng, Nitu Bansal, Sushil Kumar, Raymond B. Birge, Stefan G. Sarafianos, William J. Welsh |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Carcinogenesis Transplantation Heterologous Mice SCID Article Piperazines Mice 03 medical and health sciences Mice Inbred NOD Cell Line Tumor Neoplasms Proto-Oncogene Proteins Animals Humans Protein Kinase Inhibitors Binding Sites Multidisciplinary c-Mer Tyrosine Kinase Chemistry GAS6 Body Weight Receptor Protein-Tyrosine Kinases Isoxazoles MERTK Axl Receptor Tyrosine Kinase Small molecule 3. Good health Transplantation 030104 developmental biology Ectodomain Cell culture Cancer research Intercellular Signaling Peptides and Proteins Tyrosine kinase TYRO3 |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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