Abstract 348: Small molecule Axl Ig1-Gas6 inhibitors block Gas6-inducible Axl signaling and suppress tumorigenicity

Abstract

Abstract TAM receptors (Tyro-3, Axl, and Mer) are a family of three homologous receptor tyrosine kinases (RTKs) expressed predominantly on myeloid-derived hematopoietic cells and epithelial cells which function as inhibitory receptors that dampen inflammatory responses and maintain tissue tolerance. Additionally, all three TAMs have been implicated in various human malignancies, where level of expression is often associated with more aggressive staging of the cancers, poorer predicted patient survival, as well as drug-resistant cancers. Over the past several years, considerable effort has been made to generate small molecule tyrosine kinase inhibitors and biological therapeutics (such as monoclonal antibodies and soluble extracellular receptor traps) targeting TAM receptors in human cancers. Early preclinical studies show promising anti-tumor activities using either kinase inhibitors or monoclonal antibodies against Axl and Mer, although cross-reactivity with other tyrosine kinase inhibitors is associated with off-target specificities. Here, we report the development and characterization of a series of small molecule inhibitors that target the interface between the Ig1 domain of Axl and Gas6, and inhibit native receptors and Axl reporter lines with sub-micro-molar affinities. Additionally, these compounds inhibit Gas6 inducible motility and invasion in Axl-expressing cell lines, and suppress tumor growth in xenograft models of non small cell lung cancer. Together, these observations demonstrate that Axl can be targeted by small molecules that bind to the Ig1 domain/Gas6 interaction, and validate Ig1 inhibitors as novel agents for treatment of cancer. Citation Format: Nitu Bansal, Stanley Kimani, Kamlendra Singh, Thomas Comollo, Sushil Kumar, Vladyslav Kholodovych, Youyi Peng, William Welsh, Bertino Joseph, Raymond B. Birge. Small molecule Axl Ig1-Gas6 inhibitors block Gas6-inducible Axl signaling and suppress tumorigenicity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 348.