2. Academic Validation
  3. Small molecule inhibitors block Gas6-inducible TAM activation and tumorigenicity

Small molecule inhibitors block Gas6-inducible TAM activation and tumorigenicity

  • Sci Rep. 2017 Mar 8;7:43908. doi: 10.1038/srep43908.
Stanley G Kimani 1,  Sushil Kumar 1,  Nitu Bansal 2,  Kamalendra Singh 3,  Vladyslav Kholodovych 4 5,  Thomas Comollo 1,  Youyi Peng 2,  Sergei V Kotenko 1,  Stefan G Sarafianos 3,  Joseph R Bertino 2,  William J Welsh 2 5,  Raymond B Birge 1
Affiliations

Affiliations

  • 1 Rutgers University, New Jersey Medical School, Department of Microbiology, Biochemistry and Molecular Genetics, Cancer Center, 205 South Orange Ave, Newark, NJ 07103, USA.
  • 2 Rutgers University, Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA.
  • 3 Department of Molecular Microbiology and Immunology, and Department of Biochemistry, Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA.
  • 4 Rutgers University, Office of Advanced Research Computing, 96 Frelinghuysen Road, Piscataway, NJ 08854, USA.
  • 5 Rutgers University, Robert Wood Johnson Medical Center, Department of Pharmacology, 675 Hoes Lane, Piscataway, NJ 08854, USA.
PMID: 28272423 DOI: 10.1038/srep43908
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.

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