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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Compounds bind covalently to cysteine 12 in the switch II pocket of GDP-bound KRASG12C, preventing oncogenic signaling and causing tumor regressions in preclinical models.
“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 <sup>G12C</sup> Inhibition in Cancer (2021) · cites this paper as [3]
The paper’s structural and cellular-results passages support covalent binding at cysteine 12 in the switch-II pocket of GDP-bound KRAS(G12C) and impaired signaling-related interactions. They do not support potent tumor regressions in preclinical models: the reported effects are in lung cancer cell lines, and the discussion says the compounds require further optimization before in vivo assessment. The relevant passages have no page numbers in our copy. (LLM, conf=0.91)
Experimental — accuracy not yet measuredDiscovery of the switch-II pocket enabled development of covalent KRAS G12C inhibitors such as sotorasib and adagrasib.
“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]
The paper’s Abstract describes identifying the switch-II pocket and using it to develop early irreversible, mutant-specific KRAS G12C inhibitors. It presents those findings as a starting point for future drug discovery, but our copy does not identify sotorasib or adagrasib or establish a specific link to their development. (LLM, conf=0.87)
Experimental — accuracy not yet measuredEarly iterations of this compound were selective for the GDP-bound state, effectively locking KRAS G12C in its inactive form.
“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]
The paper reports preferential binding to GDP-bound K-Ras(G12C), irreversible inhibitor binding, and reduced GTP affinity. It says these effects should lead to accumulation in the inactive state; it does not establish that the compounds lock all treated KRAS G12C in that state. The deciding passages are in the paper’s main text (indexed under Abstract; page unavailable). (LLM, conf=0.83)
Experimental — accuracy not yet measuredCovalent inhibitors targeting mutated cysteine residues in KRASG12C exploited a binding pocket in the switch II domain which enabled the development of clinically active small molecule inhibitors for patients with this mutation.
“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]
The supplied passages (labelled Abstract; no page given) describe mutant-cysteine-targeting inhibitors that bind a switch-II pocket in K-Ras(G12C). They do not establish clinically active inhibitors for patients: the paper says its compounds still needed optimization before in vivo assessment and could serve as a starting point for drug discovery. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDirect small-molecule inhibitors of KRAS, including covalent inhibitors of KRASG12C, impair oncogenic signaling and cause tumor regressions in preclinical models.
“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]
The paper reports irreversible, mutant-specific K-Ras(G12C) inhibitors that impair effector binding and reduce viability in G12C-mutant lung cancer cell lines (Abstract; page not provided). It does not report tumor regressions: the authors describe in vivo assessment as a future step. (LLM, conf=0.91)
Experimental — accuracy not yet measured
Concomitant RTK inhibition can increase the efficacy of KRAS G12C covalent inhibitors by maintaining KRAS G12C in a GDP-bound conformation, facilitating binding of the covalent inhibitor.
“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]
The paper’s Abstract (page unavailable) reports preferential binding of the inhibitors to GDP-bound K-Ras(G12C) and says GTP loading impairs modification. It does not report that concomitant RTK inhibition maintains the GDP-bound state or increases covalent-inhibitor efficacy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredKRAS G12C is the most therapeutically tractable allele because the mutant cysteine residue enables covalent inhibitor binding within the switch-II pocket.
“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]
The Abstract and co-crystal structure passage (page numbers not supplied) show that inhibitors bind the mutant Cys 12 and extend into the switch-II pocket. The paper does not compare KRAS alleles to establish that G12C is the most therapeutically tractable. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThese inhibitors covalently bind the reactive sulfhydryl residues on the mutated cysteine located at G12, rendering them specific to the G12C mutation.
“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]
In 2013, Kevan Shokat's group introduced a class of compounds specifically designed to target KRAS G12C.
“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]
KRAS G12C inhibitors established proof-of-concept for direct KRAS inhibition.
“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 2013, Shokat and co-workers discovered a strategy using covalent inhibitors to bind to the cysteine of KRASG12C mutation and screened out lead compounds 6H05 and 2E07 using tethering.
“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 structure-activity relationship research of 6H05 derivatives, a new allosteric pocket S-IIP was identified in KRAS and exploited in further structural optimization.
“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 simulated cell conditions, after incubation for 2 h, the substrate competitive binding of SML-8-73-1 was more than 95% KRASG12C.
“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]
SML-8-73-1 contains two negatively charged phosphate groups, making it difficult to cross the cell membrane.
“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]
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.
“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]
Subsequently, several oral KRASG12C inhibitors were optimized and introduced.
“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]
Covalent PPI inhibitors were identified against RAS G12C.
“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]
Ostrem and colleagues identified a druggable allosteric binding pocket adjacent to the switch-II region of the KRAS G12C mutant protein.
“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.”
The switch-II pocket exhibits allele-specific accessibility absent in wildtype KRAS and other KRAS mutants, enabling selective pharmacological targeting of the KRAS G12C oncoprotein.
“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.”
Allosteric binding and cysteine-12 modification traps KRASG12C in the inactive state, preventing SOS-mediated GTP nucleotide exchange and impairing RAF effector protein binding.
“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).”
KRASG12C can be targeted by small-molecule inhibitors.
“was recently found to be targetable by small-molecule inhibitors (8, 9).”
Binding of cysteine-reactive compounds to K-RasG12C induces structurally disordered switch I/II, which converts the GTP preference of naive K-RasG12C to GDP.
“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]
The crystallographic structure of K-RasG12C covalently bound by cysteine-reactive compounds revealed a special allosteric switch II pocket not apparent in naive K-RasG12C protein.
“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]
Compound 12 covalently modified the mutant K-RasG12C protein.
“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]
A large fraction of K-RasG12C protein is trapped in the inactive GDP-bound state, impairing its interaction with downstream effectors such as RAF.
“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]
KRASG12C is currently 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.
“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 2013, the Shokat laboratory screened 480 tethering compounds and identified compounds that bound covalently and selectively to KRASG12C-GDP; X-ray crystallography showed binding to an expanded switch 2 pocket created by displacement of Q61 by the mutant cysteine.
“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]
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 [70]
Binding at the allosteric pocket under the Switch II loop region inhibits RAS activity by blocking SOS-mediated nucleotide exchange and altering the affinity of KRAS for GDP versus GTP.
“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]
Small molecules bind irreversibly with high specificity to the mutant cysteine at exon 12, leading to preferential GDP binding over GTP.
“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]
Covalent inhibitors that block mutant KRAS G12C were successfully developed.
“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 2013, an allosteric cysteine drug-binding pocket was discovered in GDP-bound mutant KRAS G12C protein.
“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]
Ostrem et al. developed multiple covalent inhibitors that bind to the cysteine residue at switch-II pocket of the KRAS-GDP complex, causing conformational change at switch I and switch II, preventing activation and downstream signaling, and inducing cell apoptosis.
“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]
These covalent inhibitors did not block the GTP-bound state and require intrinsic GTPase hydrolysis of KRAS G12C to the GDP-bound state for activity.
“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]
The switch II pocket was only seen in G12C-mutant protein, making it a target for drug development.
“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]
Covalent cross-linking to codon 12 cysteine induces a conformational fit and traps KRASG12C in its inactive GDP-bound state.
“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]
The previous perception that mutant KRAS was persistently locked in its active GTP-bound state might not be true.
“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]
ARS853 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.
“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]
Ostrem et al. developed a strategy to target mutant KRASG12C specifically without affecting the wild-type protein using tethering.
“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]
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 [37]
Compound 12, the first mutant-selective covalent KRAS(G12C) inhibitor, was found by tethering 480 disulfide fragments against GDP-bound KRAS(G12C).
“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]
KRAS lacks accessible pockets for reversible inhibitors, competitive inhibitors face picomolar GTP/GDP affinity, and wild-type KRAS inhibitors could cause on-target toxicity.
“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]
Covalent binding can be maintained in tethering by replacing the disulfide with an electrophile such as an acrylamide, as in the initial covalent KRAS(G12C) inhibitors.
“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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- 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
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