A Chemically Remodeled Cellular Chaperone Targets Active State Mutant KRAS

Inhibitors that target the inactive state of KRAS^G12C have demonstrated clinical benefit, but the depth and duration of response to these inhibitors are limited, and the development of new small-molecule inhibitors that target the active state of KRAS has proven difficult due to the lack of suitable binding pockets on its surface. In an effort to target the active state of KRAS, Schulze, Seamon, Zhao, and colleagues used a natural product–inspired approach that engages an immunophilin ligand to design RMC-4998, a small molecule that remodels the surface of the immunophilin cyclophilin A (CYPA) to generate a neomorphic interface that binds to the active state of mutant KRAS, specifically KRAS^G12C, with high affinity and selectivity. CYPA:RMC-4998 covalently engages with KRAS^G12C, leading to the formation of a stable tricomplex that was not detected with GDP-loaded KRAS^G12C, consistent with selectivity for the active state. Moreover, no effect on wild-type KRAS, NRAS, or HRAS was observed. Additionally, effector binding to active KRAS was rapidly disrupted by tricomplex formation, and further investigation revealed that this disruption led to the inhibition of downstream oncogenic ERK signaling with faster kinetics than the current inhibitors that bind to the inactive state of mutant KRAS. Receptor tyrosine kinase stimulation was also shown to minimally affect RMC-4998 activity, supporting the distinct biological properties of this active state–selective tricomplex inhibitor as compared to current inactive state–selective inhibitors used in the clinic. Optimization of RMC-4998 for clinical testing led to the development of RMC-6291, and daily oral use of RMC-6291 demonstrated near complete tumor regression in a human lung cancer cell line–derived xenograft model in mice. Potent antitumor activity was also observed across a panel of cell line–derived and patient-derived xenograft models of KRAS^G12C-mutant lung and colorectal cancers. In summary, the results of this study reveal that this tricomplex inhibitory strategy effectively leads to the inhibition of mutant KRAS, supporting the investigation of RMC-6291 in ongoing clinical trials in patients with solid tumors bearing a KRAS^G12C mutation, and suggest that this approach could be used to inhibit other “undruggable” targets in cancer in the future.

Schulze CJ, Seamon KJ, Zhao Y, Yang YC, Cregg J, Kim D, et al. Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS. Science 2023;381:794–9.

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