Inhibition and degradation of NRAS with a pan-NRAS monobody

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• RAS family GTPases are frequently mutated oncogenes in human cancers, with NRAS mutations common in melanoma.
• Activating NRAS mutations drive tumor growth, and effective NRAS-specific therapies are currently lacking.
• Resistance to BRAF inhibitors in melanoma often involves NRAS mutations, highlighting the need for NRAS-targeted treatments.

Purpose of the Study:

• To develop novel inhibitors targeting NRAS GTPases.
• To create a therapeutic agent effective against NRAS mutations in a mutation-agnostic manner.
• To explore the potential of NRAS inhibitors in overcoming resistance to existing cancer therapies.

Main Methods:

• Development of a novel monobody through protein engineering.
• Characterization of monobody binding to both GDP- and GTP-bound states of NRAS.
• Assessment of NRAS-mediated signaling inhibition by the monobody.
• Engineering the monobody into a genetically encoded NRAS-specific degrader.

Main Results:

• A monobody was successfully developed that specifically binds to NRAS in both GDP- and GTP-bound states.
• The monobody effectively inhibits NRAS-mediated signaling in a mutation-agnostic fashion.
• The monobody can be formatted as a genetically encoded NRAS-specific degrader, demonstrating therapeutic potential.

Conclusions:

• The study demonstrates the feasibility of developing NRAS-selective inhibitors.
• The novel monobody represents a promising therapeutic strategy for cancers with NRAS mutations.
• This work addresses a critical unmet need for NRAS-targeted pharmacologics in oncology.