Evolution of KRAS molecular glues: from allele-selective to Pan-RAS and protein-protein interaction modulators

The successful development of KRAS^G12C mutation-specific covalent inhibitors made direct targeting of KRAS a reality, yet the limitations in mutational coverage and susceptibility to resistance have spurred the pursuit of broader and more durable strategies. This review highlights the most recent developments on innovative strategies beyond traditional inhibitors, including molecular glues (MGs) and protein-protein interaction (PPI) modulators. Molecular glues, such as the RMC macrocyclic series (e.g., RMC-6291 as a G12C-selective MG, RMC-6236 as a pan-MG), function by recruiting endogenous chaperone proteins to form ternary complexes that sterically block KRAS-effector interactions or allosterically restore GTPase activity. This macrocyclic platform enables rational design of mutation-selective and broad-spectrum MGs. Another parallel advancement involves the design of small molecular MGs to strengthen KRAS engagement with E3 ligases (e.g., NEDD4-1 or LZTR1), thereby resulting in enhanced PPI or degradation of KRAS. Complementarily, PPI inhibitors (e.g., BBO-10203, VVD-699) disrupt critical oncogenic interfaces between KRAS and PI3Kα, offering a strategy to inhibit oncogenic signaling with fewer side effects. Collectively, balancing broad-spectrum versus selective targeting of KRAS, attaining optimal drug-like properties and establishing rational combination therapies with other modalities remain key challenges. The ongoing evolution of MGs and PPI modulators heralds a major expansion of the therapeutic frontier for KRAS-driven cancers and is redrawing the boundaries of precision oncology.