Selective and noncovalent targeting of RAS mutants for inhibition and degradation

Activating mutants of RAS are commonly found in human cancers, but to date selective targeting of RAS in the clinic has been limited to KRAS(G12C) through covalent inhibitors. Here, we report a monobody, termed 12VC1, that recognizes the active state of both KRAS(G12V) and KRAS(G12C) up to 400-times more tightly than wild-type KRAS. The crystal structures reveal that 12VC1 recognizes the mutations through a shallow pocket, and 12VC1 competes against RAS-effector interaction. When expressed intracellularly, 12VC1 potently inhibits ERK activation and the proliferation of RAS-driven cancer cell lines in vitro and in mouse xenograft models. 12VC1 fused to VHL selectively degrades the KRAS mutants and provides more extended suppression of mutant RAS activity than inhibition by 12VC1 alone. These results demonstrate the feasibility of selective targeting and degradation of KRAS mutants in the active state with noncovalent reagents and provide a starting point for designing noncovalent therapeutics against oncogenic RAS mutants. Most oncogenic RAS mutants remain undruggable. Here, the authors developed monobodies that selectively recognize the active state of KRAS(G12V) and KRAS(G12C) and demonstrated their utility in inhibiting RAS functions through inhibition and degradation.

Automated summary

A monobody named 12VC1 that can selectively recognize and bind to the active state of KRAS mutants has been discovered in this study, showing great potential in inhibiting the proliferation of RAS-driven cancer cell lines. This finding suggests a new strategy for treating oncogenic RAS mutants through inhibition and degradation.