Anti-Angiogenic and Tumorcidal Drugs Against Lung Carcinoma

DESCRIPTION (provided by applicant): Lung cancer is the world's leading cause of cancer deaths, with conventional therapies offering very limited benefit. Therefore, novel therapeutic approaches to improve outcomes of this disease are critical. Recent adva nces in tumor cell biology have led to renewed interest and heightened optimism in the development of new therapeutics targeting receptor tyrosine kinases, given their essential roles in tumor growth, invasion, metastasis and angiogenesis. In particular, c -Met, the receptor tyrosine kinase for hepatocyte growth factor/scatter factor (HGF/SF), has been identified as a therapeutic target against tumorigenesis. c-Met is over-expressed or mutated in a variety of solid tumors. There is strong evidence that c-Met is overexpressed, activated, and sometimes mutated in lung cancer cell lines and tumor tissues. Binding of SF/HGF to its receptor promotes growth not only of tumor cells, but also of the endothelial cells lining the tumor neovasculature. Antagonism of the c-Met-SF/HGF pathway represents an attractive tumoricidal and anti- angiogenic approach and such a bi-faceted mechanism potentially can lower the incidence of therapy-induced resistance. Our preliminary studies have identified ANG-797, an active, small mo lecule kinase inhibitor that competes with ATP for the ATP-binding site of c-Met. Encouraging results indicate that ANG-797 significantly and selectively inhibits c-Met activation and inhibits downstream signaling events initiated by SF/HGF. In vitro, ANG- 797 inhibits endothelial and tumor cell growth and SF/HGF-induced angiogenesis. In vivo data reveal a significant survival benefit to animals bearing orthotopically implanted brain tumors after i.p. or oral administration of ANG-797. Recent studies have de monstrated that ANG-797 also inhibits activity of a second RTK associated with angiogenesis, Tie-2, and the dual inhibitory activities of the compound towards these RTKs may account for the high level of anti-tumor activity in vivo despite high nanomolar i n vitro IC50s towards the individual tumor growth-related RTK targets. We believe that the potency of ANG-797 can be improved by rationally modifying substituents on its 2,4-diaminoquinazoline scaffold. Recently, by using molecular modeling and medicinal c hemistry approaches, we have generated 103 new ANG-797 analogs: thirty-seven 2- positional analogs and Sixty-six modified at the 4-position. These modifications allow expansion of this series of compounds and the potential to significantly decrease the IC5 0 against the kinase targets. Among the newer compounds, ANG-1490 and ANG-2201 have increased potency against both targets in our cell-based screening assays. Interestingly, our pilot in vivo studies suggest that ANG-1490 and ANG-2201 are efficacious again st subcutaneous NSCLC A549 tumors. In the current application, we propose to confirm the improved levels of selectivity and potency of ANG-1490 and ANG-2201 in multiple screens, and fully evaluate the anti-lung cancer effects of these compounds on the prol iferation and signal transduction in lung cancer cell lines. In addition, any newer analogs emerging from our ongoing chemistry program with the same or better potency and selectivity will be included in these evaluations. We will also determine the minima l effective dose and better understand the mechanism of action in vitro. The proposed in vivo studies will provide important preclinical efficacy data regarding the ability of these anti-angiogenic and tumorcidal agents to inhibit lung tumor growth and pro long survival in mouse models. These initial studies will support the ongoing development of a new drug with potential clinical benefits to a disease urgently needing better interventions. The high death rate of lung cancer and the lack of an effective the rapy stress the need for novel therapeutics. Small molecule inhibitors against c-Met as anti-tumor and anti-angiogenic agents have important therapeutic pot