Gluing GAP to RAS Mutants: A New Approach to an Old Problem in Cancer Drug Development

Abstract: Mutated genes may lead to cancer development in numerous tissues. While more than 600 cancer-causing genes are known today, some of the most widespread mutations are connected to the RAS gene: RAS mutations are found in approximately 25% of all human tumors. Specifically, KRAS mutations are involved in the three most lethal cancers in U.S.: pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, and lung adenocarcinoma. These cancers are among the most difficult to treat, and they are frequently excluded from chemotherapeutic attacks as hopeless cases. The mutated KRAS proteins have specific 3-dimensional conformations, which perturb functional interaction with the GAP protein on the GAP:RAS complex surface leading to a signaling cascade and uncontrolled cell growth. Here we describe a gluing docking method for finding small molecules that bind to both the GAP and the mutated KRAS molecules. These small molecules glue together the GAP and the mutated KRAS molecules and may serve as new cancer drugs for the most lethal, most difficult-to-treat carcinomas. As a proof of concept, we identify two new, drug-like small molecules with the new method: these compounds specifically inhibit the growth of PANC-1 cell line with KRAS mutation G12D in vitro and in vivo. Importantly, the two new compounds show significantly lower IC50 and higher specificity against the G12D KRAS mutant as compared to the recently described MRTX-1133 inhibitor against the G12D KRAS mutant.