Abstract 2716: Discovery of novel TAM family kinase inhibitors

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA TAM family (Tyro3, Axl, and Mer) of receptor tyrosine kinases mediated signaling is involved in cell survival, proliferation, migration and adhesion, vascular smooth muscle homeostasis, platelet function and erythropoiesis, and regulation of inflammatory cytokine release. These RTKs are frequently co-expressed in vascular, reproductive, nervous, and immune system in adults. TAM family kinases can be activated by vitamin K-dependent ligands GAS6 and Protein S. Tyro3, Axl, and Mer also display ectopic or overexpression in numerous cancers, including myeloid and lymphoblastic leukemias, melanoma, breast, lung, colon, liver, gastric, kidney, ovarian, uterine, and brain cancers. Therefore, they represent another class of kinase targets for development of cancer therapy. In this study, we report the discovery of a new class of potent and selective inhibitors of TAM family. These new compounds have demonstrated in vitro potency in nM range against these kinases and selectivity against other kinases in a selected panel. Many of these new compounds can dramatically reduce the pAkt levels in several cancer cell lines in a dose dependent manner. In thymidine incorporation assay, some compounds showed inhibition of cell proliferation at sub-micromolar concentrations. Furthermore, some compounds have demonstrated efficacy in colony formation assays. The most promising compounds are now being selected for in vivo proof-of-concept studies. The pharmaceutical properties of these compounds together with ADME profile were also evaluated. Taken together, the data generated so far indicates that these new inhibitors of TAM family kinases represent a new approach for cancer therapy. Citation Format: Zaihui Zhang, Rick Li, Erica Lee, Yuxiang Hu, Jun Yan, Jasbinder Sanghera. Discovery of novel TAM family kinase inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2716. doi:10.1158/1538-7445.AM2014-2716