Novel ligand to target KRas-related cancers

Unmet Need

Cancer is a serious health issue characterized by the abnormal growth of cells that invade and destroy healthy tissue. Nearly one in five human cancers features KRAS mutations, making it one of the most prevalent genetic mutations associated with cancer development. In healthy cells, KRAS serves as a crucial regulator of cell growth, acting as an on-off switch that inhibits growth proteins. However, when mutations occur, KRAS loses its ability to manage cell growth, resulting in uncontrolled growth leading to the development of cancer. The challenge of targeting the KRAS protein for cancer research and pharmaceutical treatment stems from its compact structure and lack of binding sites. Given KRAS's critical role in cancer development, there is need for a breakthrough that will enable its targeting.

Technology

Duke inventors have developed a ligand to bind KRAS. This is intended to be a molecular switch designed to turn KRAS signaling off. Specifically, inventors redesigned the binding domain of c-RAF, an effector of KRAS, through the introduction of several point mutations. Their design resulted in tighter binding between this c-RAF-derived protein and KRAS, providing direct control over the cellular growth pathway regulated by this interaction. Notably, the redesigned KRAS ligand can be customized through conjugation with different molecules to modulate the outcome of the interaction, including the direct inhibition of KRAS. They demonstrated the effectiveness of their design by testing biomolecular kinetics in real-time using a biosensor method. This ligand represents a significant milestone as the first protein capable of modulating downstream effector signaling of KRAS, demonstrating great potential to revolutionize cancer study and treatment.

Other Applications

This technology could be used in cancer science for the discovery of novel cancer mechanisms, and the screening of antineoplastic drugs. Additionally, the novel ligand itself could be modified to become a drug to treat cancer.

Advantages

• First KRAS ligand that modulates downstream effector signaling.

• Novel c-RAF effector-based ligand with the tightest binding ability to KRAS in is class.

• Ligand can be conjugated to different compounds to modify its effects.

• Direct targeting of KRAS offers an opportunity to control its cancer-causing potential.