Abstract LB-300: Small molecule modulators of MET kinase for treatment of human malignancies

Abstract

Abstract MET kinase is involved in numerous cancers including lung, melanoma and gastric. MET can not only be the oncogenic driver of the cancer cell but also is a key player in the cells ability to metastasize and invade tissues distant from the primary tumor site. It has been shown that 2 out of 3 cancers involving MET leads to a poor prognosis for patient survival. Using Deciphera Pharmaceutical's approach to kinase inhibition, compounds have been designed which effectively inhibit wild type and mutant MET kinase forms. These inhibitors are selective, including sparing of close family members AXL and RON. This presentation will highlight the attributes and development status of these compounds for treatment of human malignancy. Deciphera's MET program has afforded potent inhibitors that achieve low nanomolar inhibition of wild type MET and secondary activating mutant forms. Data will be presented on DP-4693 and DP-4756.IC50MET Kinasep-MET MKN-45MKN-45 Proliferationp-MET EBC-1EBC-1 ProliferationA549 MigrationDP-46934nM13 nM44 nM10 nM3nM260 nMDP-47566nM6nM23 nM2nM5nM21 nM DP-4693 and DP-4756 are selective, having as few as three kinases within 50 fold of MET potency. Inhibitor bound crystal structures will be shown which demonstrate the compounds mechanism of action. In addition, proliferation and MET phosphoprotein analysis performed with EBC-1 and MKN-45 cell lines have demonstrated excellent inhibitory profiles with potencies in the low nanomolar range. The compounds also inhibit HGF dependent cell motility in an A549 migration assay. In vivo evaluation of DP-4693 in an MKN-45 gastric cancer xenograft PK/PD model revealed complete target suppression at doses as low as 6 mpk. Futher studies will be presented highlighting the efficacy in both autocrine and paracrine (HGF-dependent) xenograft models. Deciphera's MET inhibitors also show acceptable ADME properties and are orally bioavailable in rat and dog using simple vehicles. These inhibitors have also been evaluated in two week toxicology studies, exhibiting excellent tolerability up to doses of 300 mpk. Further studies are ongoing to enable Development Candidate selection for progression into clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-300.