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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• RAS gene mutations, particularly KRAS, are implicated in ~25% of human tumors, driving the development of lethal cancers.
• KRAS mutations are prevalent in difficult-to-treat pancreatic, colorectal, and lung adenocarcinomas, often resistant to chemotherapy.
• Mutated KRAS proteins adopt conformations that disrupt interactions with GAP proteins, leading to uncontrolled cell proliferation.

Purpose of the Study:

• To develop a novel computational method for identifying small molecules targeting mutated KRAS.
• To discover new therapeutic agents capable of inhibiting KRAS-driven cancers.

Main Methods:

• A gluing docking method was employed to identify small molecules that bind to both mutated KRAS and GAP proteins.
• The efficacy of identified compounds was evaluated using the PANC-1 cell line, which harbors a KRAS G12D mutation.
• In vitro and in vivo studies were conducted to assess the inhibitory effects on cancer cell growth.

Main Results:

• Two novel, drug-like small molecules were identified using the gluing docking approach.
• These compounds demonstrated specific inhibition of PANC-1 cell line growth harboring the KRAS G12D mutation.
• The newly identified compounds exhibited superior efficacy and specificity compared to the known inhibitor MRTX-1133.

Conclusions:

• The gluing docking method is effective in discovering novel inhibitors for mutated KRAS.
• The identified small molecules represent promising therapeutic candidates for treating KRAS-mutant cancers, particularly pancreatic cancer.
• This approach offers a new strategy for developing drugs against previously intractable oncogenic mutations.