The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index.
K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions
Open accessAbstract
Somatic mutations in the small GTPase K-Ras are the most common activating lesions found in human cancer, and are generally associated with poor response to standard therapies. Efforts to target this oncogene directly have faced difficulties owing to its picomolar affinity for GTP/GDP and the absence of known allosteric regulatory sites. Oncogenic mutations result in functional activation of Ras family proteins by impairing GTP hydrolysis. With diminished regulation by GTPase activity, the nucleotide state of Ras becomes more dependent on relative nucleotide affinity and concentration. This gives GTP an advantage over GDP and increases the proportion of active GTP-bound Ras. Here we report the development of small molecules that irreversibly bind to a common oncogenic mutant, K-Ras(G12C). These compounds rely on the mutant cysteine for binding and therefore do not affect the wild-type protein. Crystallographic studies reveal the formation of a new pocket that is not apparent in previous structures of Ras, beneath the effector binding switch-II region. Binding of these inhibitors to K-Ras(G12C) disrupts both switch-I and switch-II, subverting the native nucleotide preference to favour GDP over GTP and impairing binding to Raf. Our data provide structure-based validation of a new allosteric regulatory site on Ras that is targetable in a mutant-specific manner.
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In the citing paper
“compounds have been identified that bind covalently to cysteine 12 within the switch II pocket of the GDP-bound form of the KRASG12C protein, preventing oncogenic signaling and causing potent tumor regressions in preclinical models.3-7”
From Acquired Resistance to KRAS G12C Inhibition in Cancer (2021) · cites this paper as [3]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“This paradigm changed following the discovery of the switch-II pocket, which enabled development of covalent KRAS G12C inhibitors such as sotorasib and adagrasib [5,6,7].”
From Precision Targeting of KRAS-Mutant Cancers: Beyond G12C Toward G12D and Pan-RAS Therapeutic Strategies (2026) · cites this paper as [5]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Early iterations of this compound were selective for the GDP-bound state, effectively locking KRAS G12C in its inactive form (Figure 3) [47].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [47]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“However, covalent inhibitors targeting the mutated cysteine residues in KRAS G12C exploited a binding pocket in the switch II domain which enabled the development of clinically active small molecule inhibitors for patients with this mutation [3-5].”
From Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor (2022) · cites this paper as [5]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Recent advances in medicinal chemistry have enabled the development of direct small-molecule inhibitors of KRAS, including covalent inhibitors of the KRASG12C protein that impair oncogenic signaling and cause tumor regressions in preclinical models (8–10).”
From Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer (2024) · cites this paper as [8]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Given this particular feature of the KRAS G12C mutant protein, the efficacy of these compounds can be increased by concomitant receptor tyrosine kinase (RTK) inhibition that further maintain KRAS G12C in a GDP-bound conformation, facilitating the binding of the covalent inhibitor(7-9).”
From EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer. (2020) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“KRAS G12C has emerged as the most therapeutically tractable allele because the mutant cysteine residue enables covalent inhibitor binding within the switch-II pocket [5,6,7].”
From Precision Targeting of KRAS-Mutant Cancers: Beyond G12C Toward G12D and Pan-RAS Therapeutic Strategies (2026) · cites this paper as [5]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“These inhibitors covalently bind the reactive sulfhydryl residues on the mutated cysteine located at G12, rendering them specific to the G12C mutation [47].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [47]
The cited source says what the claim attributes to it.
In the citing paper
“In 2013, Kevan Shokat’s group introduced a groundbreaking class of compounds specifically designed to target KRAS G12C.”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [47]
The cited source says what the claim attributes to it.
In the citing paper
“These agents established proof-of-concept for direct KRAS inhibition and represented a major proof-of-concept in precision oncology.”
From Precision Targeting of KRAS-Mutant Cancers: Beyond G12C Toward G12D and Pan-RAS Therapeutic Strategies (2026) · cites this paper as [5]
In the citing paper
“In 2013, Shokat and co-workers discovered a new strategy where they used covalent inhibitors to bind to the cysteine of KRASG12C mutation, and screened out two lead compounds, 6H05 (17) and 2E07 (18), by utilizing “tethering” technique.47,85,86”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [86]
In the citing paper
“In the research of structure-activity relationships of 6H05 derivatives, a new allosteric pocket, S-IIP, was identified in KRAS and exploited in further structural optimization.59,86”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [86]
In the citing paper
“The results showed that after incubation for 2 h, the substrate competitive binding of SML-8-73-1 was more than 95% KRASG12C.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [86]
In the citing paper
“However, SML-8-73-1 contains two negatively charged phosphate groups, making it difficult to cross the cell membrane.86,90”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [86]
In the citing paper
“Designing PPI inhibitors to block the interaction of RAS and RAS effect factors represents a promising paradigm for modulating RAS function and provides new impetus for the discovery of related drugs.86,326–329”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [86]
In the citing paper
“Subsequently, several oral KRASG12C inhibitors were optimized and introduced.86”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [86]
In the citing paper
“In one example, covalent PPI inhibitors were identified against RAS G12C [80].”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [80]
In the citing paper
“The era of targeting mutant KRAS was inaugurated in 2013 through seminal work by Ostrem and colleagues, 7 which identified a druggable allosteric binding pocket adjacent to the switch-II region of the KRAS G12C mutant protein.”
In the citing paper
“Crucially, this switch-II pocket exhibits allele-specific accessibility-absent in both wildtype KRAS and other KRAS mutants-thereby enabling selective pharmacological targeting of the KRAS G12C oncoprotein.”
In the citing paper
“Allosteric binding and cysteine-12 modification resulted in trapping of KRASG12C in the inactive state, with prevention of Son of Sevenless (SOS)–mediated GTP nucleotide exchange and the subsequent impairment of RAF effector protein binding (9).”
In the citing paper
“was recently found to be targetable by small-molecule inhibitors (8, 9).”
In the citing paper
“The binding of these compounds to K-RasG12C induces structurally disordered switch I/II, which converts the GTP preference of naive K-RasG12C to GDP.”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [3]
In the citing paper
“The crystallographic structure of K-RasG12C covalently bound by cysteine-reactive compounds revealed a special allosteric switch II pocket that is not apparent in naive K-RasG12C protein.3”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [3]
In the citing paper
“Recently, the heroic effort to target oncogenic Ras mutants has resulted in the development of several promising small-molecule cysteine-reactive inhibitors, such as compound 12, that covalently modified the mutant K-RasG12C protein.3”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [3]
In the citing paper
“Consequently, a large fraction of K-RasG12C protein is trapped in the inactive GDP-bound state, which impairs its interaction with downstream effectors, such as rapidly accelerated fibrosarcoma kinase (RAF).3,4,49”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [3]
In the citing paper
“Currently, KRASG12C is the only targetable form of KRAS mutation because the thiol group of cysteine 12 provides a unique handle that can be covalently modified by thiol-reacting small-molecule inhibitors.3”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [3]
In the citing paper
“In 2013, the laboratory of K. Shokat achieved a major breakthrough in KRAS targeting. Capitalizing on a unique disulfide-fragment-based chemical library approach, they screened 480 tethering compounds coupled to a cysteine-attacking nucleophile and identified compounds that bound covalently and selectively to KRASG12C-GDP70.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [70]
In the citing paper
“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 [70]
In the citing paper
“Binding at this pocket has been found to inhibit RAS activity by blocking SOS-mediated nucleotide exchange and altering the affinity of KRAS for GDP versus GTP nucleotide.”
From Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes (2021) · cites this paper as [16]
In the citing paper
“Small molecules bind irreversibly with high specificity to the mutant cysteine at exon 12, leading to preferential GDP binding over GTP16.”
From Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes (2021) · cites this paper as [16]
In the citing paper
“Covalent inhibitors that block mutant KRAS G12C were successfully developed and sotorasib was the first KRAS G12C inhibitor to be approved, with several more in the pipeline.”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [84]
In the citing paper
“In 2013, improved understanding of KRAS biology and newer drug designing technologies led to the crucial discovery of a cysteine drug-binding pocket in GDP-bound mutant KRAS G12C protein.”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [84]
In the citing paper
“Ostrem et al. developed multiple covalent inhibitors, which bind to the cysteine residue at switch-II pocket (S-IIP) of the KRAS-GDP complex. This leads to a conformational change at switch I and switch II regions, preventing its activation and downstream signaling, and eventually inducing cell apoptosis.”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [84]
In the citing paper
“Notably, these compounds did not block the GTP-bound state and require intrinsic GTPase hydrolysis of KRAS G12C to the GDP-bound state for activity.”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [84]
In the citing paper
“This switch II pocket was only seen in G12C-mutant protein, making it a target for drug development.”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [84]
In the citing paper
“Covalent cross-linking to codon 12 cysteine leads to an induced fit of the inhibitor in KRASG12C and trap the protein in its inactive, GDP-bound state (20–23).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [20]
In the citing paper
“This work also suggested that the previous perception of mutant KRAS was persistently locked in its active GTP-bound state might not be true.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [37]
In the citing paper
“ARS853 was developed (40), which selectively reduced KRAS-GTP levels by more than 90% and increased the in vitro hydrolytic reaction rate by 600-fold compared to the initial compound used in Ostrem et al. (37).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [37]
In the citing paper
“Ostrem et al., who, by using a novel screening technology called tethering, developed a new strategy to target mutant KRASG12C specifically without affecting the wild-type protein (37).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [37]
In the citing paper
“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 [37]
In the citing paper
“The inhibitor (compound 12 in their study) was discovered through a disulfide-fragment screening approach known as tethering, whereby a library of 480 disulfide fragments was screened against KRAS(G12C) in the GDP-bound state using intact protein mass spectrometry (MS)88,90.”
From Advances in covalent drug discovery (2022) · cites this paper as [88]
In the citing paper
“KRAS does not have accessible pockets for reversible inhibitors to bind to, competitive inhibitors would need to overcome the picomolar binding affinities of GTP and GDP, and inhibitors active against wild-type KRAS could show on-target toxicity86,88.”
From Advances in covalent drug discovery (2022) · cites this paper as [88]
In the citing paper
“but covalent binding can be maintained by replacing the disulfide with an electrophile such as an acrylamide, as in the case of the initial covalent KRAS(G12C) inhibitors88.”
From Advances in covalent drug discovery (2022) · cites this paper as [88]
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Citations
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Data from Delineating the RAS Conformational Landscape
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Metadata
- Authors
- Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A., & Shokat, K. M.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of California, San Francisco (US)
- Corresponding author
- Shokat, Kevan M.
- Venue
- Nature
- Published
- 2013-11
- Volume
- 503
- Issue
- 7477
- Pages
- 548-551
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4274051
- OpenAlex
- W2128339707
- Semantic Scholar
- 7d6a21edd0843a482abc37efa80674fdc4bc111d
- Cited by
- 2,557
- References
- 32
- Citations by year
- 2026: 290 · 2025: 284 · 2024: 319 · 2023: 264 · 2022: 282 · 2021: 231 · 2020: 185 · 2019: 128 · 2018: 121 · 2017: 119 · 2016: 133 · 2015: 109 · 2014: 85 · 2013: 2
- FWCI
- 49.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of General Medical Sciences (T32GM064337)
- 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 › Receptor Mechanisms and Signaling
- Keywords
- allosteric inhibition, switch II, switch I, oncogenic Ras mutations, structure-based drug design, crystal structure
- MeSH terms
- Allosteric Regulation, Allosteric Site, Cysteine, Guanosine Diphosphate, Guanosine Triphosphate, Humans, Lung Neoplasms, Models, Molecular, Genes, ras, Substrate Specificity, Oncogene Protein p21(ras), Apoptosis, Crystallography, X-Ray, Cell Line, Tumor, raf Kinases, Mutant Proteins, Static Electricity, Drug Discovery
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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