  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.
