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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1
Barbie, D. A., Tamayo, P., Boehm, J. S., Kim, S. Y., Moody, S. E., Dunn, I. F., Schinzel, A. C., Sandy, P., Meylan, E., Scholl, C., et al. (2009) · Nature · doi:10.1038/nature08460 · Cited by 3,922
Self-citationKRAS Mutation Status Is Predictive of Response to Cetuximab Therapy in Colorectal Cancer
Lièvre, A., Bachet, J.-B., Le Corre, D., Boige, V., Landi, B., Emile, J.-F., Côté, J.-F., Tomasic, G., Penna, C., Ducreux, M., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-0191 · Cited by 2,229
KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib
Pao, W. J., Wang, T. Y., Riely, G. J., Miller, V. A., Pan, Q., Ladanyi, M., Zakowski, M. F., Heelan, R. T., Kris, M. G., & VARMUS, H. E. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0020017 · Cited by 1,517
A Cytoplasmic Protein Stimulates Normal N- ras p21 GTPase, But Does Not Affect Oncogenic Mutants
Trahey, M., & McCormick, F. (1987) · Science · doi:10.1126/science.2821624 · Cited by 1,211
Milburn, M. V., Tong, L., deVos, A. M., Brünger, A. T., Yamaizumi, Z., Nishimura, S., & Kim, S. (1990) · Science · doi:10.1126/science.2406906 · Cited by 1,062
The Catalogue of Somatic Mutations in Cancer (COSMIC)
Forbes, S. A., Bhamra, G., Bamford, S., Dawson, E., Kok, C. Y., Clements, J., Menzies, A. H., Teague, J. W., Futreal, P. A., & Stratton, M. R. (2008) · Current Protocols in Human Genetics · doi:10.1002/0471142905.hg1011s57 · Cited by 899
PAI, E. F., Kabsch, W., Krengel, U., Holmes, K. C., John, J., & Wittinghofer, A. (1989) · Nature · doi:10.1038/341209a0 · Cited by 876
K-rasOncogene Activation as a Prognostic Marker in Adenocarcinoma of the Lung
Slebos, R. J. C., Kibbelaar, R. E., Dalesio, O., Kooistra, A., Stam, J., Meijer, C. J. L. M., Wagenaar, S. S., Vanderschueren, R. G. J. R. A., van Zandwijk, N., Mooi, W. J., et al. (1990) · New England Journal of Medicine · doi:10.1056/nejm199008303230902 · Cited by 806
Inhibition of NIH 3T3 Cell Proliferation by a Mutant ras Protein with Preferential Affinity for GDP
Feig, L. A., & Cooper, G. M. (1988) · Molecular and Cellular Biology · doi:10.1128/mcb.8.8.3235-3243.1988 · Cited by 799
Maurer, T., Garrenton, L. S., Oh, A., Pitts, K., Anderson, D. J., Skelton, N. J., Fauber, B. P., Pan, B., Malek, S., Stokoe, D., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1116510109 · Cited by 618
Cited by
Sorted by citations
Items 401–500 of 1,025
High-affinity interaction of the K-Ras4B hypervariable region with the RAS active site
Chavan, T. S., Jang, H., Khavrutskii, L., Abraham, S. J., Banerjee, A., Freed, B. C., Johannessen, L., Tarasov, S. G., Gaponenko, V., Nussinov, R., et al. (2015) · Biophysical Journal · doi:10.1016/j.bpj.2015.09.034 · Cited by 79
Organoid models for translational pancreatic cancer research
Tiriac, H., Plenker, D., Baker, L. A., & Tuveson, D. A. (2019) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2019.02.003 · Cited by 81
CDK1 Is a Synthetic Lethal Target for KRAS Mutant Tumours
Costa-Cabral, S., Brough, R., Konde, A., Aarts, M., Campbell, J., Marinari, E., Riffell, J. L., Bardelli, A., Torrance, C. J., Lord, C. J., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0149099 · Cited by 77
Targeting Krasg12c‐mutant cancer with a mutation‐specific inhibitor
Christensen, J. G., Olson, P., Briere, T., Wiel, C., & Bergö, M. O. (2020) · Journal of Internal Medicine · doi:10.1111/joim.13057 · Cited by 77
Drugging All RAS Isoforms With One Pocket
Kessler, D., Bergner, A., Böttcher, J., Fischer, G., Döbel, S., Hinkel, M., Müllauer, B., Weiss-Puxbaum, A., & McConnell, D. B. (2020) · Future Medicinal Chemistry · doi:10.4155/fmc-2020-0221 · Cited by 75
Direct Modulation of Small GTPase Activity and Function
Cromm, P. M., Spiegel, J., Grossmann, T. N., & Waldmann, H. (2015) · Angewandte Chemie International Edition · doi:10.1002/anie.201504357 · Cited by 80
The RAS–Effector Interaction as a Drug Target
Keeton, A. B., Salter, E. A., & Piazza, G. A. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-0938 · Cited by 77
Chemoproteomic methods for covalent drug discovery
Chan, W. C., Sharifzadeh, S., Buhrlage, S. J., & Marto, J. A. (2021) · Chemical Society Reviews · doi:10.1039/d1cs00231g · Cited by 80
MYC and KRAS cooperation: from historical challenges to therapeutic opportunities in cancer
Casacuberta‐Serra, S., González-Larreategui, Í., Capitán-Leo, D., & Soucek, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01907-z · Cited by 84
Advancing Covalent Ligand and Drug Discovery beyond Cysteine
Kim, G., Grams, R. J., & Hsu, K. (2025) · Chemical Reviews · doi:10.1021/acs.chemrev.5c00001 · Cited by 84
Ral GTPases: crucial mediators of exocytosis and tumourigenesis
Shirakawa, R., & Horiuchi, H. (2015) · Journal of Biochemistry · doi:10.1093/jb/mvv029 · Cited by 76
Choi, H., Deng, J., Li, S., Silk, T., Dong, L., Brea, E. J., Houghton, S., Redmond, D., Zhong, H., Boiarsky, J., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.03.066 · Cited by 72
Whittaker, S. R., Cowley, G. S., Wagner, S., Luo, F., Root, D. E., & Garraway, L. A. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0136-t · Cited by 75
Therapeutics Targeting Mutant KRAS
Thein, K. Z., Biter, A. B., & Hong, D. S. (2020) · Annual Review of Medicine · doi:10.1146/annurev-med-080819-033145 · Cited by 76
Selection of Nucleotide-Encoded Mass Libraries of Macrocyclic Peptides for Inaccessible Drug Targets
Colas, K., Bindl, D., & Suga, H. (2024) · Chemical Reviews · doi:10.1021/acs.chemrev.4c00422 · Cited by 80
Direct Attack on RAS: Intramolecular Communication and Mutation-Specific Effects
Marcus, K., & Mattos, C. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2148 · Cited by 75
A bright future for KRAS inhibitors
Bar-Sagi, D., Knelson, E. H., & Sequist, L. V. (2020) · Nature Cancer · doi:10.1038/s43018-019-0016-8 · Cited by 74
A Structure is Worth a Thousand Words: New Insights for RAS and RAF Regulation
Simanshu, D. K., & Morrison, D. K. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1494 · Cited by 70
Treatment Strategies for KRAS-Mutated Non-Small-Cell Lung Cancer
O’Sullivan, É., Keogh, A., Henderson, B., Finn, S. P., Gray, S. G., & Gately, K. A. (2023) · Cancers · doi:10.3390/cancers15061635 · Cited by 84
MEK inhibitors under development for treatment of non-small-cell lung cancer
Kim, C. G., & Giaccone, G. (2017) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2018.1415324 · Cited by 73
Current Approaches in NSCLC Targeting K-RAS and EGFR
Aran, V., & Omerović, J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20225701 · Cited by 74
Drugging K-RasG12C through covalent inhibitors: Mission possible?
Ni, D., Li, X., He, X., Zhang, H., Zhang, J., & Lu, S. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.06.007 · Cited by 73
Progress in the Treatment of Metastatic Pancreatic Cancer and the Search for Next Opportunities
Ko, A. H. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.59.7625 · Cited by 74
Ramms, D. J., Raimondi, F., Arang, N., Herberg, F. W., Taylor, S. S., & Gutkind, J. S. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000269 · Cited by 73
The expanding repertoire of covalent warheads for drug discovery
Mehta, N. V., & Degani, M. S. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103799 · Cited by 78
Protein Domain-Level Landscape of Cancer-Type-Specific Somatic Mutations
Yang, F., Petsalaki, E., Rolland, T., HILL, D. E., Vidal, M., & Roth, F. P. (2015) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1004147 · Cited by 71
PI3K: A Crucial Piece in the RAS Signaling PuzzlePreprint
Krygowska, A. A., & Castellano, E. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031450 · Cited by 79
Inhibitors of Ras–SOS Interactions
Lu, S., Jang, H., Zhang, J., & Nussinov, R. (2016) · ChemMedChem · doi:10.1002/cmdc.201500481 · Cited by 72
Palma, G., Khurshid, F., Lu, K., Woodward, B., & Husain, H. (2021) · npj Precision Oncology · doi:10.1038/s41698-021-00237-5 · Cited by 72
Jonckheere, N., Vasseur, R., & SEUNINGEN, I. V. (2017) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2017.01.002 · Cited by 73
Drugging the Undruggable: Advances on RAS Targeting in Cancer
Molina‐Arcas, M., Samani, A., & Downward, J. (2021) · Genes · doi:10.3390/genes12060899 · Cited by 76
Creating MHC-Restricted Neoantigens with Covalent Inhibitors That Can Be Targeted by Immune Therapy
Hattori, T., Maso, L., Araki, K. Y., Koide, A., Hayman, J., Akkapeddi, P., Bang, I., Neel, B. G., & Koide, S. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-1074 · Cited by 72
Discovery of KRAS(G12D) selective degrader ASP3082
Yoshinari, T., Nagashima, T., Ishioka, H., Inamura, K., Nishizono, Y., Tasaki, M., Iguchi, K., Suzuki, A., Sato, C., Nakayama, A., et al. (2025) · Communications Chemistry · doi:10.1038/s42004-025-01662-4 · Cited by 78
Development of Synthetic Lethality Anticancer Therapeutics
Fang, B. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm500415t · Cited by 73
Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery
Hallenbeck, K. K., Turner, D., Renslo, A. R., & Arkin, M. R. (2016) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026616666160719163839 · Cited by 73
Site-specific processing of Ras and Rap1 Switch I by a MARTX toxin effector domain
Antic, I., Biancucci, M., Zhu, Y., Gius, D. R., & Satchell, K. J. F. (2015) · Nature Communications · doi:10.1038/ncomms8396 · Cited by 72
Adaptive stress signaling in targeted cancer therapy resistance
Pazarentzos, E., & Bivona, T. G. (2015) · Oncogene · doi:10.1038/onc.2015.26 · Cited by 73
Targeted Covalent Modification Strategies for Drugging the Undruggable Targets
Tamura, T., Kawano, M., & Hamachi, I. (2025) · Chemical Reviews · doi:10.1021/acs.chemrev.4c00745 · Cited by 75
Nras in melanoma: Targeting the undruggable target
Mandalà, M., Merelli, B., & Massi, D. (2014) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2014.05.005 · Cited by 74
Li, Z., Prakash, P., & Buck, M. (2018) · ACS Central Science · doi:10.1021/acscentsci.7b00593 · Cited by 71
Araujo, H. A., Pechuan-Jorge, X., Zhou, T., Do, M. T., Hu, X., Rojas Alvarez, F. R., Salvatierra, M. E., Ibarguen, H. P., Lee, R., Raghulan, R., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-0421 · Cited by 70
The rise of covalent proteolysis targeting chimeras
Gabizon, R., & London, N. (2021) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2020.12.003 · Cited by 71
Targeting KRAS: The Elephant in the Room of Epithelial Cancers
Merz, V., Gaule, M., Zecchetto, C., Cavaliere, A., Casalino, S., Pesoni, C., Contarelli, S., Sabbadini, F., Bertolini, M., Mangiameli, D., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.638360 · Cited by 74
Accessory proteins of the RAS-MAPK pathway: moving from the side line to the front line
Pudewell, S., Wittich, C., Jasemi, N. S. K., Bazgir, F., & Ahmadian, M. R. (2021) · Communications Biology · doi:10.1038/s42003-021-02149-3 · Cited by 75
A structural model of a Ras–Raf signalosome
Mysore, V. P., Zhou, Z.-W., Ambrogio, C., Li, L., Kapp, J. N., Lu, C., Wang, Q., Tucker, M. R., Okoro, J. J., Nagy‐Davidescu, G., et al. (2021) · Nature Structural & Molecular Biology · doi:10.1038/s41594-021-00667-6 · Cited by 69
The next-generation KRAS inhibitors…What comes after sotorasib and adagrasib?
Oya, Y., Imaizumi, K., & Mitsudomi, T. (2024) · Lung Cancer · doi:10.1016/j.lungcan.2024.107886 · Cited by 73
Targeting KRAS: from metabolic regulation to cancer treatment
Shi, Y., Zheng, H., Wang, T., Zhou, S., Zhao, S., Li, M., & Cao, B. (2025) · Molecular Cancer · doi:10.1186/s12943-024-02216-3 · Cited by 81
Prakash, P., Hancock, J. F., & Gorfe, A. A. (2015) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.24786 · Cited by 69
Targeting BRAF and RAS in Colorectal Cancer
Bellio, H., Fumet, J.-D., & Ghiringhelli, F. (2021) · Cancers · doi:10.3390/cancers13092201 · Cited by 71
Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRASG12C
Kettle, J. G., Bagal, S. K., Bickerton, S., Bodnarchuk, M. S., Boyd, S., Breed, J., Carbajo, R. J., Cassar, D. J., Chakraborty, A., Cosulich, S. C., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00369 · Cited by 69
ASD2023: towards the integrating landscapes of allosteric knowledgebase
He, J., Liu, X., Zhu, C., Zha, J., Li, Q., Zhao, M., Wei, J., Li, M., Wu, C., Wang, J., et al. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad915 · Cited by 69
Computer-Aided Drug Discovery for Undruggable Targets
Sun, Q., Wang, H., Xie, J., Wang, L., Mu, J., Li, J., Ren, Y., & Lai, L. (2025) · Chemical Reviews · doi:10.1021/acs.chemrev.4c00969 · Cited by 72
Selective Targeting of the KRAS G12C Mutant: Kicking KRAS When It’s Down
Hobbs, G. A., Wittinghofer, A., & Der, C. J. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.02.015 · Cited by 69
Bartolini, A., Cardaci, S., Lamba, S., Oddo, D., Marchiò, C., Cassoni, P., Amoreo, C. A., Corti, G., Testori, A., Bussolino, F., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-2664 · Cited by 68
Riedl, J. M., Fece de la Cruz, F., Lin, J. J., Parseghian, C., Kim, J. E., Matsubara, H., Barnes, H., Caughey, B., Norden, B. L., Morales-Giron, A. A., et al. (2025) · Annals of Oncology · doi:10.1016/j.annonc.2025.01.020 · Cited by 68
Gao, Q., Ouyang, W., Kang, B., Han, X., Xiong, Y., Ding, R., Li, Y., Wang, F., Huang, L., Chen, L., et al. (2020) · Theranostics · doi:10.7150/thno.42325 · Cited by 72
Along the allostery stream: Recent advances in computational methods for allosteric drug discovery
Ni, D., Chai, Z., Wang, Y., Li, M., Yu, Z., Liu, Y., Lu, S., & Zhang, J. (2021) · Wiley Interdisciplinary Reviews Computational Molecular Science · doi:10.1002/wcms.1585 · Cited by 68
Covalent Aurora A regulation by the metabolic integrator coenzyme A
Tsuchiya, Y., Byrne, D. P., Burgess, S. G., Bormann, J., Baković, J., Huang, Y., Zhyvoloup, A., Yu, B. Y. K., Peak‐Chew, S., Tran, T. X. M., et al. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101318 · Cited by 68
RAS-ON inhibition overcomes clinical resistance to KRAS G12C-OFF covalent blockade
Nokin, M., Mira, A., Patrucco, E., Ricciuti, B., Cousin, S., Soubeyran, I., José, S. S., Peirone, S., Caizzi, L., Michelina, S. V., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-51828-2 · Cited by 70
Bifunctional Small‐Molecule Ligands of K‐Ras Induce Its Association with Immunophilin Proteins
Zhang, Z., & Shokat, K. M. (2019) · Angewandte Chemie International Edition · doi:10.1002/anie.201910124 · Cited by 66
Self-citationComprehensive Clinical and Molecular Characterization of KRASG12C-Mutant Colorectal Cancer
Henry, J. T., Coker, O., Chowdhury, S., Shen, J. P., Morris, V. K., Dasari, A., Raghav, K., Nusrat, M., Kee, B., Parseghian, C., et al. (2021) · JCO Precision Oncology · doi:10.1200/po.20.00256 · Cited by 66
Vatansever, S., Erman, B., & Gumus, Z. H. (2020) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2020.04.003 · Cited by 67
Recent progress in covalent warheads for in vivo targeting of endogenous proteins
Shindo, N., & Ojida, A. (2021) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2021.116386 · Cited by 69
Applications of covalent chemistry in targeted protein degradation
Lu, D., Yu, X., Lin, H., Cheng, R., Monroy, E. Y., Qi, X., Wang, M. C., & Wang, J. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00362g · Cited by 69
Response and Resistance to RAS Inhibition in Cancer
Ebright, R. Y., Dilly, J., Shaw, A. T., & Aguirre, A. J. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-25-0349 · Cited by 76
Exploring Cryptic Pockets Formation in Targets of Pharmaceutical Interest with SWISH
Comitani, F., & Gervasio, F. L. (2018) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.8b00263 · Cited by 67
Santarpia, M., Ciappina, G., Spagnolo, C. C., Squeri, A., Passalacqua, M. I., Aguilar, A., Gonzalez-Cao, M., Giovannetti, E., Silvestris, N., & Rosell, R. (2023) · Translational Lung Cancer Research · doi:10.21037/tlcr-22-639 · Cited by 65
Identification of Covalent Bromodomain Binders through DNA Display of Small Molecules
Daguer, J., Zambaldo, C., Abegg, D., Barluenga, S., Tallant, C., Müller, S., Adibekian, A., & Winssinger, N. (2015) · Angewandte Chemie International Edition · doi:10.1002/anie.201412276 · Cited by 65
Disease-Causing Mutations in the G Protein Gαs Subvert the Roles of GDP and GTP
Hu, Q., & Shokat, K. M. (2018) · Cell · doi:10.1016/j.cell.2018.03.018 · Cited by 65
Self-citationWang, Y., Ji, D., Lei, C., Chen, Y., Qiu, Y., Li, X., Li, M., Ni, D., Pu, J., Zhang, J., et al. (2021) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2021.01.044 · Cited by 64
Structure based virtual screening: Fast and slow
Varela‐Rial, A., Majewski, M., & Fabritiis, G. D. (2021) · Wiley Interdisciplinary Reviews Computational Molecular Science · doi:10.1002/wcms.1544 · Cited by 71
The tumour microenvironment in pancreatic cancer — new clinical challenges, but more opportunities
Kung, H., Zheng, K., Zimmerman, J. W., & Zheng, L. (2025) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-025-01077-z · Cited by 86
Ricciuti, B., Leonardi, G. C., Metro, G., Grignani, F., Paglialunga, L., Bellezza, G., Baglivo, S., Mencaroni, C., Baldi, A., Zicari, D., et al. (2015) · Expert Review of Respiratory Medicine · doi:10.1586/17476348.2016.1115349 · Cited by 65
Yoda, S., Dagogo‐Jack, I., & Hata, A. N. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.08.007 · Cited by 68
An engineered protein antagonist of K-Ras/B-Raf interaction
Kauke, M. J., Traxlmayr, M. W., Parker, J. A., Kiefer, J. D., Knihtila, R., McGee, J., Verdine, G., Mattos, C., & Wittrup, K. D. (2017) · Scientific Reports · doi:10.1038/s41598-017-05889-7 · Cited by 64
Progress in targeting RAS with small molecule drugs
McCormick, F. P. (2019) · Biochemical Journal · doi:10.1042/bcj20170441 · Cited by 64
Targeting Endogenous K-RAS for Degradation through the Affinity-Directed Protein Missile System
Röth, S., Macartney, T., Konopacka, A., Chan, K.-H., Zhou, H., Queisser, M. A., & Sapkota, G. P. (2020) · Cell chemical biology · doi:10.1016/j.chembiol.2020.06.012 · Cited by 67
Wang, K., Liu, Y., Li, J., Xiao, C., Wang, Y., Gu, W., Li, Y., Xia, Y., Yan, T., Yang, M.-H., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33761-4 · Cited by 64
Rocca, A., Braga, L., Volpe, M. C., Maiocchi, S., & Generali, D. (2022) · Cancers · doi:10.3390/cancers14215306 · Cited by 71
The era of high-quality chemical probes
Licciardello, M. P., & Workman, P. (2022) · RSC Medicinal Chemistry · doi:10.1039/d2md00291d · Cited by 61
Cregg, J., Pota, K., Tomlinson, A. C. A., Yano, J. K., Marquez, A., Liu, Y., Schulze, C. J., Seamon, K. J., Holderfield, M. T., Wei, X., et al. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c02313 · Cited by 69
Hu, C., Dadon, T., Chenna, V., Yabuuchi, S., Bannerji, R., Booher, R., Strack, P. R., Azad, N. S., Nelkin, B. D., & Maitra, A. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0028 · Cited by 65
Small Molecule KRAS Agonist for Mutant KRAS Cancer Therapy
Xu, K., Park, D., Magis, A. T., Zhang, J., Zhou, W., Sica, G., Ramalingam, S. S., Curran, W. J., & Deng, X. (2019) · Molecular Cancer · doi:10.1186/s12943-019-1012-4 · Cited by 71
Stopping the beating heart of cancer: KRAS reviewed
Herdeis, L., Gerlach, D., McConnell, D. B., & Kessler, D. (2021) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2021.06.013 · Cited by 65
Fragment-based drug discovery supports drugging ‘undruggable’ protein–protein interactions
Wang, Z.-Z., Shi, X.-X., Huang, G.-Y., Hao, G., & Yang, G. (2023) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2023.01.008 · Cited by 66
Zimmermann, G., Schultz‐Fademrecht, C., Küchler, P., Murarka, S., Ismail, S., Triola, G., Nußbaumer, P., Wittinghofer, A., & Waldmann, H. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm500632s · Cited by 64
Rational Design of Small Molecule Inhibitors Targeting the Ras GEF, SOS1
Evelyn, C. R., Duan, X., Biesiada, J., Seibel, W. L., Meller, J., & Zheng, Y. (2014) · Chemistry & Biology · doi:10.1016/j.chembiol.2014.09.018 · Cited by 63
Hodges, T. R., Abbott, J. R., Little, A. J., Sarkar, D., Salovich, J. M., Howes, J. E., Akan, D. T., Sai, J., Arnold, A. L., Browning, C. F., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01108 · Cited by 62
Assigning functionality to cysteines by base editing of cancer dependency genes
Li, H., Ma, T., Remsberg, J. R., Won, S. J., DeMeester, K. E., Njomen, E., Ogasawara, D., Zhao, K. T., Huang, T. P., Lu, B., et al. (2023) · Nature Chemical Biology · doi:10.1038/s41589-023-01428-w · Cited by 62
Lau, H. Y., Ramanujulu, P. M., Guo, D., Yang, T., Wirawan, M., Casey, P. J., Go, M., & Wang, M. (2014) · Cancer Biology & Therapy · doi:10.4161/cbt.29692 · Cited by 63
Overcoming Resistance to Drugs Targeting KRAS Mutation
Jiao, D., & Yang, S. (2020) · The Innovation · doi:10.1016/j.xinn.2020.100035 · Cited by 61
Targeting KRAS Mutant in Non-Small Cell Lung Cancer: Novel Insights Into Therapeutic Strategies
Désage, A.-L., Léonce, C., Swalduz, A., & Ortiz‐Cuaran, S. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.796832 · Cited by 65
Evaluation of the selectivity and sensitivity of isoform- and mutation-specific RAS antibodies
Waters, A. M., Ozkan‐Dagliyan, I., Vaseva, A. V., Fer, N. D., Strathern, L. A., Hobbs, G. A., Tessier‐Cloutier, B., Gillette, W., Bagni, R., Whiteley, G., et al. (2017) · Science Signaling · doi:10.1126/scisignal.aao3332 · Cited by 62
Parker, J. A., & Mattos, C. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031427 · Cited by 63
Wang, J., Martin-Romano, P., Cassier, P., Johnson, M., Haura, E., Lenox, L., Guo, Y., Bandyopadhyay, N., Russell, M., Shearin, E., et al. (2022) · The Oncologist · doi:10.1093/oncolo/oyab080 · Cited by 60
Allosteric inhibition of antiapoptotic MCL-1
Lee, S., Wales, T. E., Escudero, S., Cohen, D. T., Luccarelli, J., Gallagher, C. G., Cohen, N. A., Huhn, A. J., Bird, G. H., Engen, J. R., et al. (2016) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3223 · Cited by 59
Zhao, Q., Peng, C. Y., Huang, H., Liu, S., Zhong, Y., Huang, W., He, G., & Han, B. (2018) · Chemical Communications · doi:10.1039/c8cc04732d · Cited by 60
Machine learning approaches in predicting allosteric sites
Nerín-Fonz, F., & Cournia, Z. (2024) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2024.102774 · Cited by 62
Protein lipidation in cancer: mechanisms, dysregulation and emerging drug targets
Tate, E. W., Soday, L., de la Lastra, A. L., Wang, M., & Lin, H. (2024) · Nature reviews. Cancer · doi:10.1038/s41568-024-00666-x · Cited by 63
Ragotte, R. J., Dhanrajani, A. D., Pleydell-Pearce, J., Bel, K. L. D., Tarailo‐Graovac, M., van Karnebeek, C., Terry, J., Senger, C., McKinnon, M. L., Seear, M. D., et al. (2017) · Clinical Immunology · doi:10.1016/j.clim.2016.12.006 · Cited by 61
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 ›
Are you an author, or do you see a problem with this page? Request a review
