Small molecules for Kirsten rat sarcoma viral oncogene homolog mutant cancers: Past, present, and future

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are prevalent in over 20% of human cancers, particularly lung, colorectal, and pancreatic types.
• KRAS acts as a central regulator in cell growth pathways, linking epidermal growth factor receptor (EGFR) to downstream MAPK and AKT signaling.
• Historically considered undruggable due to its lack of a binding pocket, KRAS is now a focus for targeted therapies.

Purpose of the Study:

• To summarize the evolution of KRAS inhibitors, including small molecules, proteolysis-targeting chimeras (PROTACs), and tri-complexes.
• To discuss the challenges and future opportunities in developing novel KRAS-targeted therapeutics.
• To provide insights for the advancement of new medications targeting KRAS mutations.

Main Methods:

• Review of current literature on KRAS inhibitor development.
• Analysis of approved KRAS G12C inhibitors (Sotorasib, Glecirasib) and emerging therapeutic strategies.
• Exploration of resistance mechanisms and novel drug modalities.

Main Results:

• Three KRAS inhibitors targeting the G12C mutation are approved, with Sotorasib and Glecirasib being notable examples.
• Emerging therapeutic approaches like tri-complexes and PROTACs are being developed to overcome limitations of current inhibitors.
• Drug resistance and limited clinical benefits highlight the need for next-generation KRAS-targeted therapies.

Conclusions:

• Despite progress, challenges remain in developing effective and durable KRAS inhibitors.
• Further research into KRAS G12D and multi-target inhibitors is crucial.
• Novel strategies like PROTACs and tri-complexes offer promising avenues for overcoming resistance and improving patient outcomes in KRAS-driven cancers.