Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS
Open accessAbstract
The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require innovative strategies for therapeutic targeting. KRAS is the most frequently activated oncogene in cancer, and the active state of mutant KRAS is such a recalcitrant target. We designed a natural product–inspired small molecule that remodels the surface of cyclophilin A (CYPA) to create a neomorphic interface with high affinity and selectivity for the active state of KRAS G12C (in which glycine-12 is mutated to cysteine). The resulting CYPA:drug:KRAS G12C tricomplex inactivated oncogenic signaling and led to tumor regressions in multiple human cancer models. This inhibitory strategy can be used to target additional KRAS mutants and other undruggable cancer drivers. Tricomplex inhibitors that selectively target active KRAS G12C or multiple RAS mutants are in clinical trials now (NCT05462717 and NCT05379985).
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In xenograft models, RMC-6291 outperformed adagrasib in reducing tumor volume, which paved the way for clinical trials in patients with KRAS G12C-driven tumors.
“In xenograft models, RMC-6291 outperformed adagrasib in reducing tumor volume, which paved the way for clinical trials in patients with KRAS G12C-driven tumors.”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [64]
The Results section ('Potent anti-tumor activity in cell line and patient-derived xenografts'; page not supplied) reports tumor regression with RMC-6291 and greater potency than adagrasib in a cancer cell-line panel, but does not report that RMC-6291 outperformed adagrasib in reducing xenograft tumor volume. The Discussion (page not supplied) says a phase I/II trial of RMC-6291 is ongoing; it does not establish that a xenograft comparison paved the way for the trial. (LLM, conf=0.88)
Experimental — accuracy not yet measuredClinical trials of multiple KRASG12C inhibitors have shown promising efficacy in advanced, previously treated NSCLC, leading to FDA accelerated approval of adagrasib and sotorasib.
“Clinical trials of multiple KRASG12C inhibitors have shown promising efficacy in advanced, previously treated non–small cell lung cancer (NSCLC), leading to United States Food and Drug Administration (FDA) accelerated approval of two of these therapies (adagrasib and sotorasib) and many others being investigated in this setting (9–17).”
From Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer (2024) · cites this paper as [16]
The indexed Abstract reports that 37–43% of patients with KRASG12C-mutant NSCLC respond to sotorasib or adagrasib, supporting the claim of promising clinical efficacy. Our copy does not establish that those patients had advanced, previously treated disease or that the trials led to FDA accelerated approval of either drug. (LLM, conf=0.83)
Experimental — accuracy not yet measuredA pan-KRAS CYPA-recruiting compound, RMC-6236, is currently undergoing clinical trial.
“Additionally, a pan-KRAS CYPA-recruiting compound, RMC-6236, is currently undergoing clinical trial [64].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [64]
An alternative strategy targeting mutant KRAS G12C involves molecular glue compounds that create a complex between mutant KRAS G12C and a non-canonical binding partner cyclophilin A (CYPA).
“An alternative strategy targeting mutant KRAS G12C involves molecular glue compounds that create a complex between mutant KRAS G12C and a non-canonical binding partner cyclophilin A (CYPA) [64].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [64]
In contrast to sotorasib and adagrasib, which lock KRAS in the inactive conformation, RMC-6291 binds active KRAS-GTP.
“In contrast to sotorasib and adagrasib, which lock KRAS in the inactive conformation, RMC-6291 binds active KRAS-GTP.”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [64]
The CYPA recruiter RMC-6291 forms an inhibitory tri-complex with KRAS G12C and CYPA, resulting in a steric blockade of effector activation, including RAF.
“The CYPA recruiter RMC-6291 forms an inhibitory tri-complex with KRAS G12C and CYPA, resulting in a steric blockade of effector activation, including RAF.”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [64]
Active-state RASG12C inhibitors form a tri-complex with cyclophilin A and GTP-bound KRASG12C, to which a covalent bond is formed.
“We investigated a class of active-state RASG12C inhibitors which forms a tri-complex with the abundant intracellular protein cyclophilin A and with GTP-bound KRASG12C to which a covalent bond is formed19.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [19]
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“Saturating mutagenesis screens and looking for point mutations in KRAS that produced resistance to CYPA recruiting compound RMC-6291 identified E31A, D33A, or E37A as resistance mutations that in combination decreased drug efficacy.”
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“By contrast, RM-018 and RMC-4998 directly bind to GTP-bound KRAS G12C which results in more rapid and sustained inhibition 19 .”
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- Authors
- Schulze, C. J., Seamon, K. J., Zhao, Y., Yang, Y. C., Cregg, J., Kim, D., Tomlinson, A., Choy, T. J., Wang, Z., Sang, B., Pourfarjam, Y., Lucas, J., Cuevas-Navarro, A., Ayala-Santos, C., Vides, A., Li, C., Marquez, A., Zhong, M., Vemulapalli, V., Weller, C., Gould, A., Whalen, D. M., Salvador, A., Milin, A., Saldajeno-Concar, M., Dinglasan, N., Chen, A., Evans, J., Knox, J. E., Koltun, E. S., Singh, M., Nichols, R., Wildes, D., Gill, A. L., Smith, J. A. M., & Lito, P.
- Affiliations
- Revolution Medicines (United States) (US)
- Memorial Sloan Kettering Cancer Center (US)
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer, New York, NY 10065, USA.
- Corresponding author
- Schulze, Christopher J.
- Seamon, Kyle J.
- Zhao, Yulei
- Smith, Jacqueline A. M.
- Lito, Piro
- ORCID
- Schulze, Christopher J.
- Seamon, Kyle J.
- Zhao, Yulei
- Yang, Yu C.
- Kim, Dongsung
- Tomlinson, Aidan
- Choy, Tiffany J.
- Wang, Zhican
- Sang, Ben
- Pourfarjam, Yasin
- Lucas, Jessica
- Cuevas-Navarro, Antonio
- Ayala-Santos, Carlos
- Vides, Alberto
- Li, Chuanchuan
- Marquez, Abby
- Zhong, Mengqi
- Vemulapalli, Vidyasiri
- Weller, Caroline
- Gould, Andrea
- Salvador, Anthony
- Milin, Anthony
- Dinglasan, Nuntana
- Chen, Anqi
- Knox, John E.
- Koltun, Elena S.
- Singh, Mallika
- Wildes, David
- Gill, Adrian L.
- Smith, Jacqueline A. M.
- Lito, Piro
- Venue
- Science
- Published
- 2023-08-18
- Volume
- 381
- Issue
- 6659
- Pages
- 794-799
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC10474815
- OpenAlex
- W4385931420
- Cited by
- 264
- References
- 46
- Citations by year
- 2026: 79 · 2025: 92 · 2024: 85 · 2023: 8
- FWCI
- 23.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Pew Charitable Trusts
- Damon Runyon Cancer Research Foundation (P30 CA008748)
- Memorial Sloan-Kettering Cancer Center (CA008748, P30 CA008748)
- Pershing Square Sohn Cancer Research Alliance (P30 CA008748)
- Revolution Medicines
- National Institutes of Health (CA008748)
- National Cancer Institute (R01CA230267, CA008748, P30CA008748, R01CA279264, R01CA230745)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- KRAS G12C, cyclophilin A, molecular chaperones, small molecule inhibitors, undruggable targets, RAS mutations, oncogenic signaling, tumor regression
- MeSH terms
- Biological Products, Cysteine, Humans, Neoplasms, Signal Transduction, Proto-Oncogene Proteins p21(ras), Molecular Chaperones, Immunophilins, Cyclophilin A
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