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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
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
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Parise, A., Cresca, S., & Magistrato, A. (2024) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2024.2387856 · Cited by 27
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Nyíri, K., Koppány, G., & Vértessy, B. G. (2020) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09914-6 · Cited by 27
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Liu, J., Sun, M., Cho, K. B., Gao, X., & Guo, B. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.105304 · Cited by 28
Long, M. J. C., Rogg, C., & Aye, Y. (2020) · Accounts of Chemical Research · doi:10.1021/acs.accounts.0c00537 · Cited by 24
Erlanson, D. A., & Webster, K. R. (2021) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2021.02.010 · Cited by 28
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Han, C. W., Jeong, M. S., & Jang, S. B. (2021) · Cells · doi:10.3390/cells10040842 · Cited by 27
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Blosser, S. L., Sawyer, N., Maksimovic, I., Ghosh, B., & Arora, P. S. (2021) · ACS Chemical Biology · doi:10.1021/acschembio.1c00389 · Cited by 27
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Adachi, Y., Kimura, R., Hirade, K., & Ebi, H. (2021) · Cancers · doi:10.3390/cancers13205081 · Cited by 28
Cáceres-Gutiérrez, R. E., Alfaro‐Mora, Y., Andonegui, M. A., Díaz‐Chávez, J., & Herrera, L. A. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.751367 · Cited by 28
Khan, H. Y., Nagasaka, M., Li, Y., Aboukameel, A., Uddin, M. H., Sexton, R. E., Bannoura, S. F., Mzannar, Y., Hallak, M. N. A., Kim, S. H., et al. (2022) · Cancer Research Communications · doi:10.1158/2767-9764.crc-21-0176 · Cited by 27
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Wang, G., Bai, Y., Cui, J., Zong, Z., Gao, Y., & Zheng, Z. (2022) · Molecules · doi:10.3390/molecules27175710 · Cited by 28
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Downward, J. (2014) · Cancer Cell · doi:10.1016/j.ccr.2013.12.016 · Cited by 27
Oncogene withdrawal engages the immune system to induce sustained cancer regression
Casey, S. C., Li, Y., Fan, A. C., & Felsher, D. W. (2014) · Journal for ImmunoTherapy of Cancer · doi:10.1186/2051-1426-2-24 · Cited by 27
Anti-helminthic niclosamide inhibits Ras-driven oncogenic transformation via activation of GSK-3
Ahn, S. Y., Yang, J. H., Kim, N. H., Lee, K., Cha, Y. H., Yun, J. S., Kang, H. E., Lee, Y., Choi, J., Kim, H. S., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.16255 · Cited by 28
Biophysical screening in fragment-based drug design: a brief overview
Robson‐Tull, J. (2018) · Bioscience Horizons The International Journal of Student Research · doi:10.1093/biohorizons/hzy015 · Cited by 27
Khrenova, M. G., Kulakova, A. M., & Nemukhin, A. V. (2020) · Organic & Biomolecular Chemistry · doi:10.1039/d0ob00071j · Cited by 26
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Long, S.-A., Amparo, A. M., Goodhart, G., Ahmad, S. A., & Waters, A. M. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1402128 · Cited by 31
Tedeschi, A., Schischlik, F., Rocchetti, F., Popow, J., Ebner, F., Gerlach, D., Geyer, A., Santoro, V., Boghossian, A. S., Rees, M. G., et al. (2024) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-24-0386 · Cited by 28
Innovative design and potential applications of covalent strategy in drug discovery
Tang, T., Luo, J., Zhang, D., Lü, Y., Liao, W., & Zhang, J. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.117202 · Cited by 27
Current status of the development of Ras inhibitors
Shima, F., Matsumoto, S., Yoshikawa, Y., Kawamura, T., Isa, M., & Kataoka, T. (2015) · The Journal of Biochemistry · doi:10.1093/jb/mvv060 · Cited by 28
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Park, S. J., More, S., Murtuza, A., Woodward, B. D., & Husain, H. (2016) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2016.08.010 · Cited by 26
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Tew, B. Y., Durand, J. K., Bryant, K. L., Hayes, T. K., Peng, S., Tran, N. L., Gooden, G. C., Buckley, D. N., Der, C. J., Baldwin, A. S., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-66797-x · Cited by 29
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Chabloz, A., Schaefer, J. V., Kozieradzki, I., Cronin, S. J. F., Strebinger, D., Macaluso, F., Wald, J., Rabbitts, T. H., Plückthun, A., Marlovits, T. C., et al. (2020) · Communications Biology · doi:10.1038/s42003-020-1072-4 · Cited by 26
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Kumar, S. U., & Doss, C. G. P. (2021) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2021.104946 · Cited by 26
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Molecular Biology and Therapeutic Perspectives for K-Ras Mutant Non-Small Cell Lung Cancers
Cekani, E., Epistolio, S., Dazio, G., Cefalì, M., Wannesson, L., Frattini, M., & Froesch, P. (2022) · Cancers · doi:10.3390/cancers14174103 · Cited by 27
Wallon, L., Khan, I., Teng, K. W., Koide, A., Zuberi, M., Li, J., Ketavarapu, G., Traaseth, N. J., O’Bryan, J. P., & Koide, S. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2204481119 · Cited by 24
Multiple Strategies to Develop Small Molecular KRAS Directly Bound Inhibitors
Zhou, X., Ji, Y., & Zhou, J. (2023) · Molecules · doi:10.3390/molecules28083615 · Cited by 27
CRISPR prime editing for unconstrained correction of oncogenic KRAS variants
Jang, G., Kweon, J., & Kim, Y. (2023) · Communications Biology · doi:10.1038/s42003-023-05052-1 · Cited by 30
Yang, L., Li, Z., Binzel, D. W., Guo, P., & Williams, T. M. (2023) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2023.07.027 · Cited by 29
Synthetic Approaches to the New Drugs Approved During 2021
McInturff, E. L., France, S. P., Leverett, C. A., Flick, A. C., Lindsey, E. A., Berritt, S., Carney, D. W., DeForest, J. C., Ding, H. X., Fink, S. J., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00501 · Cited by 26
Direct Modulators of K-Ras–Membrane Interactions
Morstein, J., Shrestha, R., Van, Q. N., López, C. A., Arora, N., Tonelli, M., Hong, L., Chen, D., Zhou, Y., Hancock, J. F., et al. (2023) · ACS Chemical Biology · doi:10.1021/acschembio.3c00413 · Cited by 27
Self-citationChemical Biology Tools for Regulating RAS Signaling Complexity in Space and Time
van Hattum, H., & Waldmann, H. (2014) · Chemistry & Biology · doi:10.1016/j.chembiol.2014.08.001 · Cited by 27
Oncogenic K-ras confers SAHA resistance by up-regulating HDAC6 and c-myc expression
Wang, Q., Tan, R., Zhu, X. J., Zhang, Y., Tan, Z., Su, B., & Li, Y. (2016) · Oncotarget · doi:10.18632/oncotarget.7134 · Cited by 25
The spatiotemporal regulation of RAS signalling
Herrero, A., Matallanas, D., & Kölch, W. (2016) · Biochemical Society Transactions · doi:10.1042/bst20160127 · Cited by 26
Furlan, D., Trapani, D., Berrino, E., Debernardi, C., Panero, M., Libera, L., Sahnane, N., Riva, C., Tibiletti, M. G., Sessa, F., et al. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.9 · Cited by 26
Lu, H., & Martı́, J. (2020) · The Journal of Physical Chemistry Letters · doi:10.1021/acs.jpclett.0c02809 · Cited by 21
Bioactive atropisomers: Unraveling design strategies and synthetic routes for drug discovery
Liu, S., Zhao, Q., Liu, X., Gamble, A. B., Huang, W., Yang, Q., & Han, B. (2024) · Medicinal Research Reviews · doi:10.1002/med.22037 · Cited by 29
Borsatto, A., Gianquinto, E., Rizzi, V., & Gervasio, F. L. (2024) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.3c01318 · Cited by 28
Lokhandwala, J., Smalley, T. B., & Tran, T. H. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1394702 · Cited by 28
Molecular pathways and targeted therapies in head and neck cancers pathogenesis
Constantin, M., Chifiriuc, M. C., Bleoţu, C., Vrâncianu, C. O., Cristian, R.-E., Bertesteanu, S. V., Grigore, R., & Berteșteanu, G. S. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1373821 · Cited by 29
Khedkar, N. R., Sindkhedkar, M. D., & Joseph, A. (2025) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2025.108197 · Cited by 27
Optimizing drug design by merging generative AI with a physics-based active learning framework
Filella-Mercè, I., Molina, A., Díaz, L., Orzechowski, M., Berchiche, Y. A., Zhu, Y. M., Vilalta-Mor, J., Malo, L., Yekkirala, A. S., Ray, S. S., et al. (2025) · Communications Chemistry · doi:10.1038/s42004-025-01635-7 · Cited by 46
Liaki, V., Barrambana, S., Kostopoulou, M., Lechuga, C. G., Zamorano-Domínguez, E., Acosta, D., Morales-Cacho, L., Álvarez, R., Sun, P., Rosas-Pérez, B., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2523039122 · Cited by 27
RetractedInhibition of Ral GTPases Using a Stapled Peptide Approach
Thomas, J. C., Cooper, J. M., Clayton, N. S., Wang, C., White, M. A., Abell, C., Owen, D., & Mott, H. R. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.720243 · Cited by 25
Yamamoto, G., Kikuchi, M., Kobayashi, S., Arai, Y., Fujiyoshi, K., Wakatsuki, T., Kakuta, M., Yamane, Y., Iijima, Y., Mizutani, H., et al. (2017) · International Journal of Oncology · doi:10.3892/ijo.2017.3935 · Cited by 26
Zhang, Y., Wang, Z., Ma, X., Yang, S., Hu, X., Tao, J., Hou, Y., & Bai, G. (2018) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2018.11.002 · Cited by 25
Huang, Y., Wei, L., Han, X., Chen, H., Ren, Y., Xu, Y., Song, R., Rao, L., Chen, S., Peng, C., et al. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.111749 · Cited by 24
Small molecule inhibitors of RAS proteins with oncogenic mutations
Orgován, Z., & Keserű, G. M. (2020) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09911-9 · Cited by 25
Modulation of Amyloidogenic Protein Self-Assembly Using Tethered Small Molecules
Cawood, E. E., Guthertz, N., Ebo, J. S., Karamanos, T. K., Radford, S. E., & Wilson, A. J. (2020) · Journal of the American Chemical Society · doi:10.1021/jacs.0c10629 · Cited by 23
Zeng, J., Weng, J., Zhang, Y., Xia, F., Cui, Q., & Xu, X. (2021) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.1c04679 · Cited by 24
Monobodies as tool biologics for accelerating target validation and druggable site discovery
Akkapeddi, P., Teng, K. W., & Koide, S. (2021) · RSC Medicinal Chemistry · doi:10.1039/d1md00188d · Cited by 24
Plangger, A., Rath, B., Hochmair, M. J., Funovics, M. A., & Hamilton, G. (2021) · Translational Oncology · doi:10.1016/j.tranon.2021.101230 · Cited by 24
Li, H., Qi, W.-L., Wang, Y., & Meng, L. (2021) · Genes & Diseases · doi:10.1016/j.gendis.2021.08.011 · Cited by 28
Small-Molecule Inhibitors and Degraders Targeting KRAS-Driven Cancers
Hyun, S., & Shin, D. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222212142 · Cited by 26
Pan-RAS inhibitors: Hitting multiple RAS isozymes with one stone
Coley, A. B., Ward, A., Keeton, A. B., Chen, X., Maxuitenko, Y. Y., Prakash, A., Li, F., Foote, J. B., Buchsbaum, D. J., & Piazza, G. A. (2022) · Advances in cancer research · doi:10.1016/bs.acr.2021.07.009 · Cited by 23
Du, H., Jiang, D., Gao, J., Zhang, X., Jiang, L., Zeng, Y., Wu, Z., Shen, C., Xu, L., Cao, D., et al. (2022) · Research · doi:10.34133/2022/9873564 · Cited by 23
Hu, Z., & Martí, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232213865 · Cited by 25
Cell death in cancer therapy of lung adenocarcinoma
Zagryazhskaya, A., Gyurászová, K., & Zhivotovsky, B. (2015) · The International Journal of Developmental Biology · doi:10.1387/ijdb.150044bz · Cited by 25
Schulz, R., Atef, A., Becker, D., Gottschalk, F., Tauber, C., Wagner, S., Arkona, C., ABDEL‐HAFEZ, A. A., Farag, H. H. A., Rademann, J., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01440 · Cited by 25
Misra, P., & Singh, S. (2019) · Cancer Medicine · doi:10.1002/cam4.2112 · Cited by 25
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Mattox, T. E., Chen, X., Maxuitenko, Y. Y., Keeton, A. B., & Piazza, G. A. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms21010141 · Cited by 25
SRC kinase drives multidrug resistance induced by KRAS-G12C inhibition
Song, X., Zhou, Z., Elmezayen, A., Wu, R., Yu, C., Gao, B., Minna, J. D., Westover, K. D., Zeh, H. J., Kroemer, G., et al. (2024) · Science Advances · doi:10.1126/sciadv.adq4274 · Cited by 26
Zhao, D., Li, H., Mambetsariev, I., Mirzapoiazova, T., Chen, C., Fricke, J., Kulkarni, P., Villaflor, V., Arvanitis, L., Hamilton, S., et al. (2022) · Cancers · doi:10.3390/cancers14194933 · Cited by 24
A treatment strategy for KRAS-driven tumors
Mai, T. T., & Lito, P. (2018) · Nature Medicine · doi:10.1038/s41591-018-0111-x · Cited by 24
Small-molecule inhibition of MAP2K4 is synergistic with RAS inhibitors in KRAS -mutant cancers
Jansen, R. A., Mainardi, S., Dias, M. H., Bosma, A. R., van Dijk, E., Selig, R., Albrecht, W., Laufer, S., Zender, L., & Bernards, R. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2319492121 · Cited by 23
KRAS mutations in advanced non-small cell lung cancer: From biology to novel therapeutic strategies
Liguori, L., Salomone, F., Viggiano, A., Sabbatino, F., Pepe, S., Formisano, L., Bianco, R., & Servetto, A. (2024) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2024.104554 · Cited by 27
Shembrey, C., Yang, R., Casan, J. M. L., Hu, W., Chen, H., Singh, G. J., Sadras, T., Prasad, K., Shortt, J., Johnstone, R. W., et al. (2024) · Science Advances · doi:10.1126/sciadv.adl0731 · Cited by 26
Tanaka, N., & Ebi, H. (2024) · Cancer Science · doi:10.1111/cas.16441 · Cited by 26
Advances in the treatment of KRASG12C mutant non–small cell lung cancer
Shaverdashvili, K., & Burns, T. F. (2025) · Cancer · doi:10.1002/cncr.35783 · Cited by 25
Broderick, C., Mezzadra, R., Sisso, E. M., Mbuga, F., Raghulan, R., Perez, A. C., Kulick, A. R., Jiang, L., Jiang, J., Ho, Y.-J., et al. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-1425 · Cited by 28
D3S-001 in advanced solid tumors with KRASG12C mutations: a phase 1 trial
Cho, B. C., Lü, S., Lee, M. A., Song, Z., Park, J., Lim, S. M., Li, Z., Zhao, J., Richardson, G. E., Zhang, Y., et al. (2025) · Nature Medicine · doi:10.1038/s41591-025-03688-6 · Cited by 24
Qiao, X., Zhu, C., Lan, X., Li, M., Li, N., Huang, J., Liu, N., Zhang, J., & Lu, S. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c01619 · Cited by 24
Fragment-based drug discovery: A graphical review
AlKharboush, D. F., Kozielski, F., Wells, G., & Porta, E. O. J. (2025) · Current Research in Pharmacology and Drug Discovery · doi:10.1016/j.crphar.2025.100233 · Cited by 28
Changing the course of pancreatic cancer – Focus on recent translational advances
Javle, M. M., Golan, T., & Maitra, A. (2016) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2016.01.004 · Cited by 24
Small-molecule binding sites to explore protein–protein interactions in the cancer proteome
Xu, D. D., Jalal, S. I., Sledge, G. W., & Meroueh, S. O. (2016) · Molecular BioSystems · doi:10.1039/c6mb00231e · Cited by 24
Will the Real Cryptic Pocket Please Stand Out?
Amaro, R. E. (2019) · Biophysical Journal · doi:10.1016/j.bpj.2019.01.018 · Cited by 25
Chen, F.-Y., Li, X., Zhan, G., Liu, H., Kang, B., Zhang, S.-C., Peng, C. Y., & Han, B. (2020) · Tetrahedron Letters · doi:10.1016/j.tetlet.2020.151806 · Cited by 24
Whole-genome characterization of lung adenocarcinomas lacking alterations in the RTK/RAS/RAF pathway
Carrot‐Zhang, J., Yao, X., Devarakonda, S. H. K., Deshpande, A. S., Damrauer, J. S., Silva, T. C., Wong, C. K., Choi, H. Y., Felau, I., Robertson, A. G., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.108784 · Cited by 24
Synergistic effects of FGFR1 and PLK1 inhibitors target a metabolic liability in KRAS‐mutant cancer
Zhang, Y., Liang, S., Saliakoura, M., Yang, H., Vassella, E., Konstantinidou, G., Tschan, M. P., Hegedűs, B., Zhao, L., Gao, Y., et al. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202013193 · Cited by 23
KRAS G12C fragment screening renders new binding pockets
Mathieu, M., Steier, V., Fassy, F., Delorme, C., Papin, D., Genêt, B., Duffieux, F., Bertrand, T., Delarbre, L., Le-Borgne, H., et al. (2021) · Small GTPases · doi:10.1080/21541248.2021.1979360 · Cited by 24
Mahadik, N. S., Bhattacharya, D., Padmanabhan, A., Sakhare, K. R., Narayan, K. P., & Banerjee, R. (2021) · Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1755 · Cited by 26
Wang, X. (2021) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.1c00844 · Cited by 23
Zhang, Z., Wang, Y., Chen, X., Song, X., Tu, Z., Chen, Y., Zhang, Z., & Ding, K. (2021) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2021.116457 · Cited by 24
Nakayama, A., Nagashima, T., Nishizono, Y., Kuramoto, K., Mori, K., Homboh, K., Yuri, M., & Shimazaki, M. (2021) · British Journal of Cancer · doi:10.1038/s41416-021-01629-x · Cited by 24
Inhibition of Ras Signaling by Blocking Ras–Effector Interactions with Cyclic Peptides
Upadhyaya, P., Qian, Z., Selner, N. G., Clippinger, S. R., Wu, Z., Briesewitz, R., & Pei, D. (2015) · Angewandte Chemie · doi:10.1002/ange.201502763 · Cited by 24
KRAS as a Key Oncogene in the Clinical Precision Diagnosis and Treatment of Pancreatic Cancer
Dai, M., Chen, S., Teng, X., Chen, K., & Cheng, W. (2022) · Journal of Cancer · doi:10.7150/jca.76695 · Cited by 28
Eliminating oncogenic RAS: back to the future at the drawing board
Steffen, C. L., Kaya, P., Schaffner‐Reckinger, E., & Abankwa, D. (2023) · Biochemical Society Transactions · doi:10.1042/bst20221343 · Cited by 23
The choreography of protein kinase PDK1 and its diverse substrate dance partners
Leroux, A. E., & Biondi, R. M. (2023) · Biochemical Journal · doi:10.1042/bcj20220396 · Cited by 25
Passiglia, F., Reale, M. L., Russo, G. L., Pasello, G., Minuti, G., Bulotta, A., Galetta, D., Pelizzari, G., Sini, C., Bria, E., et al. (2023) · Lung Cancer · doi:10.1016/j.lungcan.2023.107444 · Cited by 24
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
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