Wireless Sensor Inserts for Combating Incontinence-Associated Dermatitis

DESCRIPTION (provided by applicant): The development of drugs that inhibit the K-Ras oncogene represents one of the greatest unmet needs in the treatment of human cancer. The Ras gene is the most frequently mutated oncogene in cancer, with a greater than 30% cumulative mutation frequency across all cancer types. Cancers with Ras mutations are aggressive and respond poorly to standard therapies. Previous attempts to target K-Ras have failed due to the difficulty of competing with the picomolar nucleotide affinity for the active sit and due to the high similarity of most GTPases. Our scientific co-founder, Professor Kevan Shokat, has discovered a novel, small molecule approach to target the most chemically tractable K-Ras mutant that contains a glycine-12 to cysteine mutation. The G12C mutation is the most common K-Ras mutation in lung cancer. Indeed, 43% of all lung cancers with K-Ras mutations contain the G12C mutation. This mutation positions a chemically reactive sulfhydryl group on the surface of K-Ras. Wehave carried out a preliminary 500 compound library screen based on mass spectrometry for molecules which bind covalently to K-rasG12C, H-rasG12C and counterscreened against WT K-Ras. 17 hits were identified from the screening library, and the first roundoptimization of the initial hits led to the discovery of a potent inhibitor JO-01-18. We have now solved the crystal structure of JO-01-148 bound to K-Ras G12C and identified a previously undescribed allosteric pocket on the surface of the protein adjacent to the cysteine moiety. This pocket makes it possible to identify irreversible inhibitors that bind in the pocket and selectively target the cysteine at position 12. Importantly, these small molecules inhibit only mutant K-Ras and not the normal protein. We have now solved more than 10 X-ray crystal structures of irreversible inhibitors bound to this allosteric pocket and synthesized more than 120 compounds. A clear SAR has been established. We are now proposing to further validate our lead G12C compounds in biochemical and cellular assays. The Phase I specific aims are: (1) Develop assays to evaluate K-Ras effector binding; (2) Demonstrate that the G12C irreversible binders can disrupt K-Ras effector binding; and (3) Demonstrate that the G12C irreversible binders can differentially affect tumor cells with G12C mutation compared to cells with wild type K-Ras and other K-Ras mutations. The Phase I milestone is the identification of K-ras G12C inhibitors that suppress proliferation of tumor cells with G12C K-ras mutation five-fold more potently (as measured by IC50 values) relative to tumor cells with other K-Ras mutations or wild type Ras. Collectively, we expect the Phase I results to demonstrate that we can generate a small molecule inhibitor that will specifically inhibit the growth of tumor cells wih K-Ras G12C mutation. If our approach is successful, our Phase II studies will more fully examine the safety, efficacy, and PK/biodistribution of a lead formulation for advancement to an IND application.PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: The K-Ras oncogene is present in gt80% of pancreatic tumors, gt40% of colon tumors and gt20% of lung tumors. Cancers with K-Ras mutations are aggressive and respond poorly to standard therapies. Thus,a drug that directly targets mutant K-Ras is highly desired to address this unmet medical need. The success of the proposed project would represent a significant advance for patients whose tumors harbor K-Ras mutations and have limited therapeutic options.