Evaluation Of Compounds Developed Against The Tam Family Kinases

The TAM family receptor tyrosine kinases, consisting of Tyro3, Axl and Mer, are implicated in a diverse range of cellular processes such as cell survival, proliferation, migration, angiogenesis, and inflammatory response. Despite the debates over their role as a driver in carcinogenesis owing to some recent findings, their link to human cancer is strongly supported by direct correlation of the level of expression/activity with tumor grade and prognosis. In particular, Axl was found to underlie metastasis as an essential regulator of the epithelial-mesenchymal transition (EMT) process and also to confer acquired resistance to the TKI-mediated targeted therapies by up-regulation of associated kinases. Currently, none of FDA-approved kinase drugs were developed for the TAM family kinases. In our effort to develop such small-molecule inhibitors targeting the TAM kinases for oncology indications, we uncovered a series of novel potent compounds with low nM potency against Axl and Tyro3. Effect of these compounds in human cancer cell lines of different tissue origins was mediated mainly through the Axl-dependent signaling pathways. Detailed analysis of signaling proteins downstream of Axl revealed different mechanisms of action for these compounds. In addition to suppression of cell proliferation, these compounds inhibited anchorage-independent colony formation, cell migration and invasion. Four compounds were selected to be evaluated in pharmacokinetic studies in mice and the results indicated that these compounds possess reasonable PK properties with high exposure, reasonably long half-life, and good bioavailability. The results of the efficacy studies in suppressing tumor growth in a xenograft and an orthotropic mouse models will be discussed. Citation Format: Hong Zhang, Zaihui Zhang, Xiaoqing Shi, Erica Lee, Rick Li, Yuxiang Hu, Jun Yan, Jasbinder Sanghera. Evaluation of compounds developed against the TAM family kinases. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5393. doi:10.1158/1538-7445.AM2015-5393