Therapeutic Targeting of Oncogenic K‐Ras by a Covalent Catalytic Site Inhibitor
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We report the synthesis of a GDP analogue, SML‐8‐73‐1, and a prodrug derivative, SML‐10‐70‐1, which are selective, direct‐acting covalent inhibitors of the K‐Ras G12C mutant relative to wild‐type Ras. Biochemical and biophysical measurements suggest that modification of K‐Ras with SML‐8‐73‐1 renders the protein in an inactive state. These first‐in‐class covalent K‐Ras inhibitors demonstrate that irreversible targeting of the K‐Ras guanine‐nucleotide binding site is potentially a viable therapeutic strategy for inhibition of Ras signaling.
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SM-10-70-1 showed increased cellular permeability and competitively inhibited KRASG12C through covalent binding.
“SM-10-70-1 showed increased cellular permeability and competitively inhibited KRASG12C through covalent binding.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [91]
SM-10-70-1 also inhibits KRAS-dependent signaling pathways such as Akt and Erk.
“In addition, KRAS-dependent signaling pathways, such as the Akt and Erk pathways, are also inhibited.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [91]
SM-10-70-1 was synthesized by modifying phosphoric acid groups of SML-8-73-1 with caging technology.
“Therefore, SM-10-70-1 (22) was synthesized by modifying phosphoric acid groups of SML-8-73-1 with “caging” technology.91”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [91]
SM-10-70-1 exhibits anti-proliferative activity in several cancer cell lines expressing the KRASG12C mutation.
“Moreover, the ability of SM-10-70-1 to exhibit anti-proliferative activity was demonstrated in several cancer cell lines expressing the KRASG12C mutation.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [91]
KRASG12C can be targeted by small-molecule inhibitors.
“was recently found to be targetable by small-molecule inhibitors (8, 9).”
SML-10-70-1 covalently modifies cysteine 12 of K-RasG12C and has anti-proliferative activity in KRASG12C mutant models.
“SML-10-70-1, a GDP-derived analog that covalently modifies cysteine 12 of K-RasG12C, was identified with anti-proliferative activity in KRASG12C mutant models.53”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [53]
SML-10-70-1 functioned as a nonspecific K-RasG12C inhibitor, as K-RasG12S-bearing cells also responded to this compound.
“However, SML-10-70-1 functioned as a nonspecific K-RasG12C inhibitor, as K-RasG12S-bearing cells also responded to this compound.53”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [53]
KRASG12C inhibitors do not affect RAS signalling in non-malignant cells and theoretically carry a low risk of on-target, off-tumour toxicity.
“Accordingly, inhibitors of this type are KRASG12C specific; therefore, they do not affect RAS signalling in non-malignant cells65,70–72 and, at least theoretically, have a low risk of on-target, off-tumour toxicities.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [72]
Lim et al. reported the synthesis of a GDP analog, SML-8-73-1, which covalently modifies cysteine 12 of KRasG12C and competes with GTP and GDP for active site binding in a cellular context.
“Lim et al. reported the synthesis of a GDP analog, SML-8-73-1, which contains an electrophilic chloroacetamide attached to the β-phosphate. This analog can covalently modify cysteine 12 of KRasG12C and, as a result, it competes with GTP and GDP for active site binding in a cellular context (38).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [38]
Earlier studies identified small molecules selectively recognizing and irreversibly inactivating one specific KRAS-mutant allele harboring a G12C amino acid substitution.
“Earlier studies have identified small molecules selectively recognizing and irreversibly inactivating one specific KRAS-mutant allele harboring a G12C amino acid substitution (37, 38).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [38]
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- Authors
- Lim, S. M., Westover, K. D., Ficarro, S. B., Harrison, R. A., Choi, H. G., Pacold, M. E., Carrasco, M., Hunter, J., Kim, N. D., Xie, T., Sim, T., Jänne, P. A., Meyerson, M., Marto, J. A., Engen, J. R., & Gray, N. S.
- Affiliations
- Harvard University (US)
- The University of Texas Southwestern Medical Center (US)
- Dana-Farber Cancer Institute (US)
- Northeastern University (US)
- Daegu-Gyeongbuk Medical Innovation Foundation (KR)
- Korea Institute of Science and Technology (KR)
- Broad Institute (US)
- Corresponding author
- Gray, Nathanael S.
- ORCID
- Venue
- Angewandte Chemie International Edition
- Publisher
- Wiley
- Published
- 2013-11-20
- Volume
- 53
- Issue
- 1
- Pages
- 199-204
- ISSN
- 1433-7851 (ISSN-L)
- 1521-3773
- PMC
- PMC3914205
- OpenAlex
- W2141965353
- Cited by
- 300
- References
- 30
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 15 · 2023: 10 · 2022: 18 · 2021: 21 · 2020: 31 · 2019: 34 · 2018: 27 · 2017: 36 · 2016: 37 · 2015: 29 · 2014: 24
- FWCI
- 13.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Angewandte Chemie International Edition (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA130876)
- National Institute of General Medical Sciences (R01GM101135, GM101135)
- National Institute of Neurological Disorders and Stroke (P01NS047572)
- 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
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- covalent inhibitors, prodrugs, Ras signaling inhibition, oncogenic Ras, small molecule inhibitors
- MeSH terms
- Drug Design, Signal Transduction, ras Proteins, Catalytic Domain
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