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 the U.S., namely 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 three-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 the 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 human pancreatic cancer
cell line PANC-1, as compared to the recently described selective G12D KRAS inhibitor
MRTX-1133.
