Abstract C199: Development of potent, small‐molecule inhibitors of ETK

Epithelial and endothelial tyrosine kinase (Etk) is a nonreceptor tyrosine kinase that plays a central role in the proliferation, differentiation, apoptosis, and tumorigenicity of epithelial cells. Inhibition of Etk signaling can result in impaired cellular transformation, down‐regulation of angiogenesis, and increased apoptosis. Employing our proprietary CLIMB™ technology, a computationally driven drug discovery process, we designed and synthesized approximately 35 small molecules for ETK‐inhibition testing in biochemical and cellular assays. Most of these compounds exhibited low nanomolar activity and selectivity across a wide panel of kinases. Five compounds were subsequently chosen for further evaluation in in vivo studies. As predicted from CLIMB™, all of the compounds showed sufficient tolerability and pharmacokinetics in mice to advance into tumor efficacy studies. Endometrial and hepatocellular cancers were selected for these studies based on previous in vitro results indicating high ETK expression and potent compound activity. All five compounds demonstrated marked activity in these models; in one cell line, two of the compounds inhibited tumor growth by more than 50% after less than two weeks of dosing. Using these same tumor lines in pharmacodynamic studies, the compounds also showed significant modulation of cellular transformation and anti‐apoptotic markers consistent with ETK inhibition. Moreover, quantitative analysis of microvessel density, a key indicator of angiogenesis, demonstrated clear inhibition of blood vessel formation from tumors excised after treatment with the five compounds. Utilizing our CLIMB™ technology, we have rapidly developed a new class of potent inhibitors that consistently demonstrate in vivo activity against ETK‐relevant tumor cell lines. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C199.