Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S)
Open accessAbstract
Drugs that directly impede the function of driver oncogenes offer exceptional efficacy and a therapeutic window. The recently approved mutant selective small-molecule cysteine-reactive covalent inhibitor of the G12C mutant of K-Ras, sotorasib, provides a case in point. KRAS is the most frequently mutated proto-oncogene in human cancer, yet despite success targeting the G12C allele, targeted therapy for other hotspot mutants of KRAS has not been described. Here we report the discovery of small molecules that covalently target a G12S somatic mutation in K-Ras and suppress its oncogenic signaling. We show that these molecules are active in cells expressing K-Ras(G12S) but spare the wild-type protein. Our results provide a path to targeting a second somatic mutation in the oncogene KRAS by overcoming the weak nucleophilicity of an acquired serine residue. The chemistry we describe may serve as a basis for the selective targeting of other unactivated serines.
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These compounds showed GDP-bound KRAS selectivity.
“These compounds showed GDP-bound KRAS selectivity.”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [59]
The Results section (‘A β-lactone ligand acylates the mutant serine’; page unavailable) explicitly reports GDP-bound-state selectivity for G12Si-1: it did not react with GppNHp-loaded K-Ras(G12S) under identical conditions. The Results section on optimized β-lactones reports reactions with GDP-bound K-Ras(G12S), but does not establish the same nucleotide-state selectivity for those other compounds. The plural claim is therefore broader than the demonstrated comparison. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThese molecules were effective at halting the growth of cells expressing KRAS G12S at concentrations greater than 10 μM.
“These molecules were effective at halting the growth of cells expressing KRAS G12S at concentrations greater than 10 μM.”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [59]
The Results section (‘Optimized β-lactone ligands suppress K-Ras(G12S) signaling’; page not available) reports that G12Si-5 inhibited growth of KRAS G12S-expressing Ba/F3 and KMS20 cells. Their reported growth-inhibition IC50 values were 2.4 µM and 7.5 µM, respectively—not greater than 10 µM—and the passage does not establish that the molecules as a group halted cell growth above 10 µM. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCompounds containing β-lactone electrophiles covalently acylate the mutant serine of G12S in the switch II pocket.
“Compounds containing β-lactone electrophiles, designed to mimic the chemistry of natural proteasome inhibitors, covalently acylate the mutant serine of G12S in the switch II pocket.”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [59]
In 2022, the Shokat lab introduced a novel KRAS G12S-selective covalent inhibitor.
“In 2022, the Shokat lab introduced a novel KRAS G12S-selective covalent inhibitor [59].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [59]
Using adagrasib as the parent core, Shokat and colleagues introduced an α,β-lactone structure that covalently targets serine and developed the first selective covalent inhibitor G12Si-5 targeting KRASG12S mutants.
“Using adagrasib as the parent core, they introduced a, β-lactone structure that can covalently target serine and successfully developed the first selective covalent inhibitor G12Si-5 (24) targeting KRASG12S mutants.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [93]
G12Si-5 binds to the S-IIP domain and inhibits oncogenic signaling, reducing ERK phosphorylation in KRASG12S mutant cells.
“G12Si-5 binds to the S-II P domain and inhibits oncogenic signaling, reducing ERK phosphorylation in KRASG12S mutant cells.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [93]
In 2022, Shokat and colleagues reported the development of covalent inhibitors of KRASG12S mutants and KRASG12R mutants.
“In 2022, Shokat and colleagues reported the development of covalent inhibitors of KRASG12S mutants and KRASG12R mutants.93,94”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [93]
The IC50 value of G12Si-5 in the A549 cell line was 2.4 μM.
“The IC50 value of G12Si-5 in A549 cell line was 2.4 μM.93”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [93]
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Targeting small GTPases: emerging grasps on previously untamable targets, pioneered by KRAS
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“Of note, KRASG12C/Y96D secondary mutation was found to disrupt Adagrasib binding, which was sufficient to retain KRAS activation in the presence of Adagrasib.483 Other secondary mutations in SII-P of KRAS discovered in a clinical study cohort (NCT03785249), including R68S, H95D, H95Q, H95R, and Y96C, were reported to…”
BackgroundInfluentialStrain-release alkylation of Asp12 enables mutant selective targeting of K-Ras-G12D
Zheng, Q., Zhang, Z., Guiley, K. Z., & Shokat, K. M. (2024) · Nature Chemical Biology · doi:10.1038/s41589-024-01565-w · Cited by 82 · see citing works
Self-citationTargeted 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 71 · see citing works
Chemical technology principles for selective bioconjugation of proteins and antibodies
Chauhan, P. S., Ragendu, V., Kumar, M., Molla, R., Mishra, S. D., Basa, S., & Rai, V. (2023) · Chemical Society Reviews · doi:10.1039/d3cs00715d · Cited by 69 · see citing works
Development of covalent inhibitors: Principle, design, and application in cancer
Zheng, L., Li, Y., Wu, D., Xiao, H., Zheng, S., Wang, G., & Sun, Q. (2023) · MedComm – Oncology · doi:10.1002/mog2.56 · Cited by 71 · see citing works
Simultaneous Covalent Modification of K-Ras(G12D) and K-Ras(G12C) with Tunable Oxirane Electrophiles
Yu, Z., He, X., Wang, R., Xu, X., Zhang, Z., Ding, K., Zhang, Z., Tan, Y., & Li, Z. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.3c05899 · Cited by 63 · see citing works
Self-citationKRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance
Ash, L. J., Busia-Bourdain, O., Okpattah, D., Kamel, A., Liberchuk, A., & Wolfe, A. L. (2024) · Current Oncology · doi:10.3390/curroncol31040150 · Cited by 59 · see citing works
“The G12C inhibitor BI-0474 scaffold was used to develop the pan-KRAS inhibitor BI-2865, which non-covalently binds to KRAS-GDP with high affinity while sparing wildtypes HRAS and NRAS [62].”
MethodInfluentialTargeting Ras-, Rho-, and Rab-family GTPases via a conserved cryptic pocket
Morstein, J., Bowcut, V., Fernando, M. C., Yang, Y., Zhu, L., Jenkins, M. L., Evans, J. T., Guiley, K. Z., Peacock, D. M., Krahnke, S., et al. (2024) · Cell · doi:10.1016/j.cell.2024.08.017 · Cited by 59 · see citing works
Self-citationKRAS Mutation Subtypes and Their Association with Other Driver Mutations in Oncogenic Pathways
Mondal, K., Posa, M. K., Shenoy, R. P., & Roychoudhury, S. (2024) · Cells · doi:10.3390/cells13141221 · Cited by 56 · see citing works
“Characterization of small molecule compound for G12S ligand, an electrophilic group, β -lactone reacts explicitly with a serine residue, which could attach with the tetrahydropyridopyrimidine moiety of G12C ligand Adagarisib [176].”
BackgroundAnnual review of KRAS inhibitors in 2022
Wang, H., Chi, L., Yu, F., Dai, H., Gao, C., Si, X., Wang, Z., Liu, L., Zheng, J., Shan, L., et al. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115124 · Cited by 48 · see citing works
Targeting KRAS in Pancreatic Ductal Adenocarcinoma: The Long Road to Cure
de Jesus, V. H. F., Mathias-Machado, M. C., de Farias, J. P. F., Aruquipa, M. P. S., Jacome, A. A. D. A., & Peixoto, R. D. (2023) · Cancers · doi:10.3390/cancers15205015 · Cited by 47 · see citing works
“Some examples of compounds tested with pan-RAS properties include 3144, which can bind to the switch-I site and prevent RAS pocket effector activation, and BI-2852 (Boehringer, Ingelheim, Germany), which acts on the DCAI pocket and reduces SOS1 activity, thereby decreasing ERK and AKT activation…”
BackgroundFacts and Hopes on RAS Inhibitors and Cancer Immunotherapy
Boumelha, J., Molina‐Arcas, M., & Downward, J. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-22-3655 · Cited by 44 · see citing works
“These include inhibitors targetingtheactiveformofKRASG12CoragainstotherKRASmutant proteins such as G12D, G12S, and G12R (22 – 24).”
BackgroundUSP7 deubiquitinates KRAS and promotes non-small cell lung cancer
Huang, B., Cao, D., Yuan, X., Xiong, Y., Chen, B., Wang, Y., Niu, X., Tian, R., & Huang, H. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114917 · Cited by 46 · see citing works
Somsen, B. A., Schellekens, R. J. C., Verhoef, C. J. A., Arkin, M. R., Ottmann, C., Cossar, P. J., & Brunsveld, L. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.2c12781 · Cited by 41 · see citing works
From bench to bedside: current development and emerging trend of KRAS-targeted therapy
Chen, Y., Liu, Q.-P., Xie, H., & Ding, J. (2023) · Acta Pharmacologica Sinica · doi:10.1038/s41401-023-01194-4 · Cited by 44 · see citing works
“For the KRAS G12S mutation, they employed a potent electrophile, β -lactone-containing molecules, to covalently modify the less reactive serine residue [87].”
New prospectives on treatment opportunities in RASopathies
Gelb, B. D., Yohe, M. E., Wolf, C. M., & Andelfinger, G. (2022) · American Journal of Medical Genetics Part C Seminars in Medical Genetics · doi:10.1002/ajmg.c.32024 · Cited by 39 · see citing works
Hoyt, K. W., Urul, D. A., Ogboo, B. C., Wittlinger, F., Laufer, S., SCHAEFER, E. M., May, E. W., & Heppner, D. E. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c01502 · Cited by 35 · see citing works
Emerging landscape of KRAS inhibitors in cancer treatment
Riedl, J. M., Matsubara, H., McNeil, R., Patel, P. S., de la Cruz, F. F., Gulhan, D., & Corcoran, R. B. (2026) · Cancer Cell · doi:10.1016/j.ccell.2026.01.001 · Cited by 40 · see citing works
RAS signaling and immune cells: a sinister crosstalk in the tumor microenvironment
Liu, Y., Xie, B., & Chen, Q. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-04486-9 · Cited by 34 · see citing works
“The chemical development of other covalent ligands of mutant arginine residue in KRAS G12R and mutant serine residue in KRAS G12S provided a novel therapeutic window specifically for KRAS-driven cancers [90, 91], although in vivo experimental evidence was incomplete.”
BackgroundA single inhibitor for all KRAS mutations
Corcoran, R. B. (2023) · Nature Cancer · doi:10.1038/s43018-023-00615-x · Cited by 36 · see citing works
Design, Synthesis, and Bioevaluation of Pyrido[2,3-d]pyrimidin-7-ones as Potent SOS1 Inhibitors
Liu, M., Zhou, G., Su, W., Gu, Y., Gao, M., Wang, K., Huo, R., Li, Y., Zhou, Z., Chen, K., et al. (2023) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.2c00490 · Cited by 33 · see citing works
Wu, X., Pan, J., Fan, R., Zhang, Y., Wang, C., Wang, G., Liu, J., Cui, M., Yue, J., Jin, R., et al. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c01712 · Cited by 34 · see citing works
Direct K-Ras Inhibitors to Treat Cancers: Progress, New Insights, and Approaches to Treat Resistance
Nussinov, R., & Jang, H. (2023) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-022823-113946 · Cited by 32 · see citing works
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 26 · see citing works
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 · see citing works
“This technology overcomes the weak nucleophilicity of an acquired serine residue, which may serve as a way to selectively target other inactivated serines in covalent drug development [62].”
BackgroundDirect 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 26 · see citing works
Self-citationHu, Z., & Martı́, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232213865 · Cited by 25 · see citing works
RAS‐targeted cancer therapy: Advances in drugging specific mutations
Liu, C., Ye, D., Yang, H., Chen, X., Su, Z., Li, X., Ding, M., & Liu, Y. (2023) · MedComm · doi:10.1002/mco2.285 · Cited by 24 · see citing works
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 26 · see citing works
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 · see citing works
Targeting KRAS Diversity: Covalent Modulation of G12X and Beyond in Cancer Therapy
Kirschner, T., Müller, M. P., & Rauh, D. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c02403 · Cited by 24 · see citing works
Insight into Janus kinases specificity: From molecular architecture to cancer therapeutics
Wei, T., Lu, M., Yao, S., Hong, Y., Yang, J., Zhang, M., Yin, Y., Han, Y., Li, Q., Wang, Z., et al. (2024) · MedComm – Oncology · doi:10.1002/mog2.69 · Cited by 22 · see citing works
Evolution of direct RAS inhibitors: from undruggable target to clinical breakthroughs
Wang, X., Wu, J., Xiao, A., Wang, J., & Tian, J. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02364-0 · Cited by 24 · see citing works
“Building upon the optimized groups of MRTX1133 and MRTX849, a variety of covalent inhibitors targeting different KRAS mutations were obtained by replacing the warhead of MRTX1133, including G12S [41] (Shokat Lab), G12R [42] (Shokat Lab), G12D/C [43] (Li Lab), G12D [44] (Shokat Lab) (Fig.”
Technologies for Direct Detection of Covalent Protein–Drug Adducts
Mons, E., Kim, R. Q., & Mulder, M. P. C. (2023) · Pharmaceuticals · doi:10.3390/ph16040547 · Cited by 23 · see citing works
Genetically Encoded Epoxide Warhead for Precise and Versatile Covalent Targeting of Proteins
Zhang, J., Wang, X., Huang, Q., Ye, J., & Wang, J. (2024) · Journal of the American Chemical Society · doi:10.1021/jacs.4c03974 · Cited by 20 · see citing works
Proteome-wide Ligand and Target Discovery by Using Strain-Enabled Cyclopropane Electrophiles
Liu, Y., Yu, Z., Li, P., Yang, T., Ding, K., Zhang, Z., Tan, Y., & Li, Z. (2024) · Journal of the American Chemical Society · doi:10.1021/jacs.4c04695 · Cited by 20 · see citing works
Self-citationMultiple medicinal chemistry strategies of targeting KRAS: State-of-the art and future directions
Shang, Y., Fu, S., Hao, Q., Ying, H., Wang, J., & Shen, T. (2024) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2023.107092 · Cited by 17 · see citing works
Bracken, A. K., Gekko, C. E., Suss, N. O., Lueders, E. E., Cui, Q., Fu, Q., Lui, A. C. W., Anderson, E. T., Zhang, S., & Abbasov, M. E. (2024) · Journal of the American Chemical Society · doi:10.1021/jacs.3c10741 · Cited by 15 · see citing works
Liu, Y., Chen, J., Li, X., Fan, Y., Peng, C. Y., Ye, X., Wang, Y. A., & Xie, X. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107577 · Cited by 17 · see citing works
Discovery of Covalent Ligands with AlphaFold3
Shamir, Y., Gabizon, R., Rogel, A., Lin, D. Y.-W., Andreotti, A. H., & London, N. (2026) · Journal of the American Chemical Society · doi:10.1021/jacs.5c22222 · Cited by 17 · see citing works
Extended Applications of Small-Molecule Covalent Inhibitors toward Novel Therapeutic Targets
Lee, J., & Park, S. B. (2022) · Pharmaceuticals · doi:10.3390/ph15121478 · Cited by 15 · see citing works
“G12Si-5 (7) GTPase (KRASG12S) Anticancer (NSCLC) β-Lactam [48]”
BackgroundKage, M., Hayashi, R., Matsuo, A., Tamiya, M., Kuramoto, S., Ohara, K., Irie, M., Chiyoda, A., Takano, K., Ito, T., et al. (2024) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2024.117830 · Cited by 15 · see citing works
Advances and Challenges in RAS Signaling Targeted Therapy in Leukemia
Chen, Y., Yin, Z., Westover, K. D., Zhou, Z., & Shu, L. (2024) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-24-0504 · Cited by 15 · see citing works
“Notably, the adagrasib scaffold has been adapted to target other oncogenic KRAS variants, such as KRAS G12S (71).”
Kocabey, S., Cattin, S., Gray, I., & Rüegg, C. (2024) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2024.116839 · Cited by 14 · see citing works
Xiao, X., Miao, X., Duan, S., Liu, S., Cao, Q., Wu, R., Tao, C., Zhao, J., Qu, Q., Markiewicz, A., et al. (2023) · Small Methods · doi:10.1002/smtd.202300096 · Cited by 13 · see citing works
Parry, C., Pellicano, F., Schüttelkopf, A. W., Beyer, K. S., Bower, J. F., Bryson, A., Cameron, K., Cerutti, N. M., Clark, J. P., Davidson, S. C., et al. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c02929 · Cited by 12 · see citing works
Herzberg, B. O., & Manji, G. A. (2023) · The Oncologist · doi:10.1093/oncolo/oyad014 · Cited by 14 · see citing works
Single-cell sensor analyses reveal signaling programs enabling Ras-G12C drug resistance
Zhang, J. Z., Ong, S., Baker, D. A., & Maly, D. J. (2024) · Nature Chemical Biology · doi:10.1038/s41589-024-01684-4 · Cited by 12 · see citing works
Hamachi, I., Tamura, T., & Nonaka, H. (2025) · Accounts of Chemical Research · doi:10.1021/acs.accounts.5c00646 · Cited by 11 · see citing works
Innovative drugs promote precision cancer therapy
Huang, X., Zhu, M., Chen, R., Ni, J., Zhao, W., Li, S., Lü, X., Jiao, H., & Cao, X. (2023) · Clinical Cancer Bulletin · doi:10.1007/s44272-023-00002-8 · Cited by 11 · see citing works
“Ziyang Zhang et al. proposed the G12Si series of drugs, a small molecule that binds irreversibly to KRAS (G12S), among which G12Si-5 exhibited the best inhibitory effect (Ki = 26 µM) [21].”
Frankovich, T. V., McCann, H. M., Hoffman, K. S., & Rullo, A. F. (2025) · ACS Central Science · doi:10.1021/acscentsci.5c00699 · Cited by 10 · see citing works
Werner, A. N., Kumar, A. I., & Charest, P. G. (2023) · Molecular Biology of the Cell · doi:10.1091/mbc.e23-05-0152 · Cited by 10 · see citing works
“In fact, many cancer cells harboring KRAS mutations were found to have low-mutant K-Ras dependency, including the A549 lung cancer cells, although these cells are still very tumorigenic (Singh et al. , 2009; Weng et al. , 2012; Fujita-Sato et al. , 2015; Zhang et al. , 2022).”
A Top-Down Proteomic Assay to Evaluate KRAS4B-Compound Engagement
D'Ippolito, R., Rabara, D., Blanco, M. A., Alberico, E. O., Drew, M. R., Ramakrishnan, N., Sontan, D., Widmeyer, S. R. T., Scheidemantle, G. M., Messing, S., et al. (2024) · Analytical Chemistry · doi:10.1021/acs.analchem.3c05626 · Cited by 7 · see citing works
Pharmacological targeting of casein kinase 1δ suppresses oncogenic NRAS-driven melanoma
Wen, Y., Wang, H., Yang, X., Zhu, Y., Li, M., Ma, X., Huang, L., Wan, R., Zhang, C., Li, S., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-54140-1 · Cited by 10 · see citing works
“…of treatment approaches has been explored in the preclinical and clinical trials, primarily focusing on inhibiting the MAPK signaling pathway 29 , either alone or in combination with interventions targeting downstream signaling pathways of NRAS, suchasCDK4/6,FAK, and autophagy pathways 30 – 33 .”
Rahmani, R., Djafri, A., Khaldi, H., Megrouss, Y., Guerroudj, A. R., Dege, N., Djafri, A., & Chouaıh, A. (2024) · Journal of Molecular Structure · doi:10.1016/j.molstruc.2024.139661 · Cited by 9 · see citing works
KRASG12D selective VHL-PROTAC with sparing KRASWT and other KRAS mutants
Jeon, E., Kim, C., Ko, M., Kim, T. K., Bae, J., Oh, J. W., Kim, K. P., Kim, H. S., & Sim, T. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.117928 · Cited by 9 · see citing works
ZBTB11 depletion targets metabolic vulnerabilities in KRAS inhibitor-resistant PDAC
Tran, N. L., Jiang, J., Ma, M., Gadbois, G. E., Gulay, K. C. M., Verano, A. L., Schiavon, C. R., Rebollo, E., Zhou, H., Huang, C., et al. (2025) · Nature Chemical Biology · doi:10.1038/s41589-025-01978-1 · Cited by 12 · see citing works
“ZBTB11 is a zinc finger (ZF) transcription factor that cooperates with GA-binding protein-α to regulate the nuclear expression of components of complex I and the mitoribosome, thereby maintaining field of research 3–7 .”
Covalent drug – An emerging framework for targeted drug development
Bhole, R. P., Joshi, G. O., Kapare, H. S., Chikhale, R. V., & Chaudhari, S. Y. (2024) · Results in Chemistry · doi:10.1016/j.rechem.2024.101615 · Cited by 9 · see citing works
In Silico Evaluation of the Thr58-Associated Conserved Water with KRAS Switch-II Pocket Binders
Leini, R., & Pantsar, T. (2023) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.2c01479 · Cited by 8 · see citing works
Graph neural networks for identifying protein-reactive compounds
Gil, V., & Rowley, C. N. (2024) · Digital Discovery · doi:10.1039/d4dd00038b · Cited by 8 · see citing works
Zhou, Y., Zhang, L., Niu, Z. L., & Wang, Z. A. (2025) · Biomolecules · doi:10.3390/biom15121699 · Cited by 7 · see citing works
“Nevertheless, these residues are functionally important: they can undergo post-translational modifications (PTMs) (e.g., H3Q5 mono-amination) [82] and play critical roles in disease-relevant mutations (e.g., KRas G12S) [83].”
Li, N., Liu, C., Zhang, W., & Rao, G. (2023) · Current Medicinal Chemistry · doi:10.2174/0109298673258913231019113814 · Cited by 7 · see citing works
Crystal structure of NRAS Q61K with a ligand-induced pocket near switch II
Gebregiworgis, T., Chan, J. Y.-L., Kuntz, D. A., Privé, G. G., Marshall, C. B., & Ikura, M. (2024) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2024.151414 · Cited by 9 · see citing works
Tan, Y. S., Chakrabarti, M., Stein, R. M., Prentis, L. E., Rizzo, R. C., Kurtzman, T., Fischer, M. M., & Balius, T. E. (2025) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.4c01623 · Cited by 6 · see citing works
“However, other residues may also be attacked, including serines, aspartates, and arginines, all of which have been targeted for RAS, 50 − 52 as well as lysines, tyrosines, threonines, and histidines.”
InfluentialSynthetic approaches and clinical application of KRAS inhibitors for cancer therapy
Jiang, M., Ma, S., Xuan, Y., & Chen, K. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.117626 · Cited by 6 · see citing works
Emerging and Established Targets in Colorectal Cancer: Translating Biology Into Therapeutics
Grochot, R. M., Bartolini, M., Algaze, S. D., Reimann, P., Winder, T., Lenz, H., & Fontana, E. (2026) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk-26-516576 · Cited by 5 · see citing works
Evolution of structure-guided drug design strategies targeting mutations in codon 12 of KRAS
Dorandish, S., Bhayekar, K., Singh, A., Kushwaha, N. D., Malin, E., Serafimovski, S., Kelm, J. M., Gavande, N. S., & Lakkaniga, N. R. (2025) · RSC Medicinal Chemistry · doi:10.1039/d5md00169b · Cited by 5 · see citing works
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Crystallographic Studies of KRAS in Complex with Small Molecules and RAS-Binding Proteins
Chan, A. H., & Simanshu, D. K. (2024) · Methods in molecular biology · doi:10.1007/978-1-0716-3822-4_5 · Cited by 5 · see citing works
Standardized Parts for Activation of Small GTPase Signaling in Living Cells
He, Y., Faulkner, B. M., Roberti, M. A., Bassford, D. K., & Stains, C. I. (2024) · Angewandte Chemie International Edition · doi:10.1002/anie.202403499 · Cited by 4 · see citing works
Distal Covalent Targeting Suppresses Signaling of Oncogenic K-Ras(G13C) in Cancer Cells
Zheng, Q., Shen, T., Pampel, J., & Shokat, K. M. (2025) · ACS Chemical Biology · doi:10.1021/acschembio.5c00249 · Cited by 4 · see citing works
Self-citationThe Oxidative Drug Combination for Suppressing KRAS G12D Inducible Tumour Growth
Бегимбетова, Д., Kukanova, А., Fazyl, F., Manekenova, K., Омаров, Т. М., Burska, A. N., Khamijan, M., Gulyayev, A., Yermekbayeva, B., Макишев, А. К., et al. (2022) · BioMed Research International · doi:10.1155/2022/9426623 · Cited by 5 · see citing works
“KRAS has been identi fi ed as the most frequently mutated gene in human cancers that is responsible for 30% of all human carcinomas [1 – 4].”
A Nexus between Genetic and Non-Genetic Mechanisms Guides KRAS Inhibitor Resistance in Lung Cancer
Kulkarni, P., Mohanty, A. R., Ramisetty, S. K., Duvivier, H. L., Khan, A., Shrestha, S., Tan, T., Merla, A., El-Hajjaoui, M., Malhotra, J. D., et al. (2023) · Biomolecules · doi:10.3390/biom13111587 · Cited by 4 · see citing works
“Small-molecule inhibitors that are either specific to G12C, such as sotorasib (AMG510) and adagrasib (MRTX849) [22–24], or that are non-G12C-specific (pan-KRAS) inhibitors, have been developed [25].”
Wang, H., Liu, D., Yu, Y., Fang, M., Gu, X., & Long, D. (2022) · Physical Chemistry Chemical Physics · doi:10.1039/d2cp04964c · Cited by 4 · see citing works
Hu, Z., & Martı́, J. (2024) · Molecular Physics · doi:10.1080/00268976.2024.2316883 · Cited by 4 · see citing works
Shen, T., Fei, W., Hu, Z., Pang, M., Ma, J., Zhou, T., & Shang, Y. (2025) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2025.109345 · Cited by 3 · see citing works
Chemical adaptation: bridging synthetic chemistry with drug development
Ding, K., Li, Y., Zhou, Y., & Huang, W. (2026) · Science China Life Sciences · doi:10.1007/s11427-025-3223-4 · Cited by 3 · see citing works
“In contrast, inorganic drugs, such as the platinum-containing agents cisplatin, carboplatin, and oxaliplatin, are designed to be more effectively delivered to tumor sites, minimizing side effects in normal tissues (Zhang et al., 2022a).”
Copper-catalyzed nitration of electron-deficient BN-naphthalene
Fang, X. (2023) · Chemical Communications · doi:10.1039/d3cc04359b · Cited by 3 · see citing works
Kidane, M., Hoffman, R. M., Wolfe-Demarco, J. K., Huang, T.-Y., Teng, C.-L., Samanta, S., Lira, L. M. G., Lin‐Jones, J., Pallares, G., Lamerdin, J. E., et al. (2024) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.4c00450 · Cited by 3 · see citing works
Martins, F., Machado, A. L., Carvalho, J., Almeida, C. R., Beck, H. C., Carvalho, A. S., Backman, V., Matthiesen, R., & Velho, S. (2025) · Scientific Reports · doi:10.1038/s41598-025-94549-2 · Cited by 3 · see citing works
Comprehensive molecular characterization of collecting duct carcinoma for therapeutic vulnerability
Guan, P., Chen, J., Mo, C., Fukawa, T., Zhang, C., Cai, X., Li, M., Hong, J. H., Chan, J. Y., Ng, C. C. Y., et al. (2024) · EMBO Molecular Medicine · doi:10.1038/s44321-024-00102-5 · Cited by 3 · see citing works
“To date, only one other genomic study focused on Chinese CDC patients ( n = 10) using formalin-fi xed, paraf fi n-embedded (FFPE) samples, which found a similar TMB with ours (1.37 vs our 1.86 per MB) (Zhang et al, 2022a).”
BackgroundInfluentialGhosh, S., Fan, F., Powell, R. T., Park, Y. S., STEPHAN, C. C., Kopetz, S., Ellis, L. M., & Bhattacharya, R. (2024) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359241303302 · Cited by 3 · see citing works
“5,6 Inhibitors targeting other specific mutations of KRAS including agents targeting G12D 7 and G12S 8 and pan-KRAS inhibitors targeting both wild-type and mutated KRAS 9,10 are under development.”
ZBTB11 Depletion Targets Metabolic Vulnerabilities in K-Ras Inhibitor Resistant PDACPreprint
Tran, N. L., Jiang, J., Ma, M., Gadbois, G. E., Gulay, K. C. M., Verano, A. L., Zhou, H., Huang, C., Scott, D. A., Bang, A. G., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.19.594824 · Cited by 3 · see citing works
Methods for Controlling Small GTPase Activity
Faulkner, B. M., He, Y., Sitrin, D., & Stains, C. I. (2025) · ChemBioChem · doi:10.1002/cbic.202500156 · Cited by 2 · see citing works
Proteomic Perspectives on KRAS-Driven Cancers and Emerging Therapeutic Approaches
Karki, R., Chen, R., & Pan, S. (2025) · Current Oncology · doi:10.3390/curroncol32110614 · Cited by 2 · see citing works
“Using competition proteomics, a proteomic after treatment with a terminal alkyne-containing analog of G12Si-5 in cells that were pretreated with G12Si-5 or DMSO, resulted in KRAS G12S being a selective target together with off-target modification on proteins PLD3, TRMT61A, and TRMT6 [100].”
Systematic cysteine scanning identifies a druggable pocket in oncogenic KRAS
van Tienen, L. M., Bayoumi, S., Muneeruddin, K., Leymarie, N., Popa, A., Shekhar, M., Mueller, M. A., Li, R., Żak, K. M., Chilukuri, H., et al. (2026) · Cell chemical biology · doi:10.1016/j.chembiol.2026.01.007 · Cited by 2 · see citing works
Phillips, D. P., Alper, P. B., Cho, C. Y., Borkin, D., Han, D., Kochanek, S. E., Vidal-Biggart, A., Herath, A., Gurjar, J., Lu, W., et al. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6c00127 · Cited by 2 · see citing works
Protein State‐Dependent Chemical Biology
Scott, K. A., Zhang, T. L., Xi, S. Y., Ngo, B., & Vinogradova, E. V. (2023) · Israel Journal of Chemistry · doi:10.1002/ijch.202200101 · Cited by 3 · see citing works
Covalency-enabled Drug Discovery is Redefining Druggability
McKenna, J. M., & Proctor, R. S. J. (2023) · CHIMIA International Journal for Chemistry · doi:10.2533/chimia.2023.537 · Cited by 2 · see citing works
Westover, K. D. (2024) · Nature Chemical Biology · doi:10.1038/s41589-024-01556-x · Cited by 2 · see citing works
Malolactone strikes: K-Ras-G12D's Achilles' heel
Adamopoulos, C., Papavassiliou, K. A., & Papavassiliou, A. G. (2024) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2024.04.001 · Cited by 2 · see citing works
Insights into direct KRAS inhibition strategies for cancer treatment
Li, T., Gu, C., Zhou, C., Mao, C., Yang, K., Xu, J., Lu, T., & Chen, J. (2024) · Future Medicinal Chemistry · doi:10.1080/17568919.2024.2424149 · Cited by 3 · see citing works
Targeting KRASG13C with cyclic linker based inhibitors to explore warhead orientation
Kirschner, T., Rodriguez, J., Moreira, E. G., Niggenaber, J., Warmuth, J. D., Verli, H., Müller, M. P., & Rauh, D. (2025) · Scientific Reports · doi:10.1038/s41598-025-22145-5 · Cited by 2 · see citing works
“Another significant mutation hotspot within the KRAS gene is codon 13, where mutations occur in approximately 14 % of tumors 16 .”
Smith, B. P., Rigby, M., Ma, R., & Maciag, A. E. (2024) · Methods in molecular biology · doi:10.1007/978-1-0716-3822-4_20 · Cited by 2 · see citing works
- Authors
- Zhang, Z., Guiley, K. Z., & Shokat, K. M.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Shokat, Kevan M.
- Venue
- Nature Chemical Biology
- Published
- 2022-07-21
- Volume
- 18
- Issue
- 11
- Pages
- 1177-1183
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC9596369
- OpenAlex
- W4286203125
- Cited by
- 153
- References
- 57
- Citations by year
- 2026: 23 · 2025: 36 · 2024: 51 · 2023: 34 · 2022: 9
- FWCI
- 10.70
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Chemical Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Samuel Waxman Cancer Research Foundation
- Howard Hughes Medical Institute
- U.S. Department of Health & Human Services | National Institutes of Health (R01CA244550)
- The Emerald Foundation The Mark Foundation
- Damon Runyon Cancer Research Foundation (DRG-2281-17, DRG-2399-20)
- 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 › Protein Degradation and Inhibitors
- Keywords
- KRAS oncogenic signaling, covalent inhibitors, small molecule inhibitors, sotorasib
- MeSH terms
- Acylation, Cysteine, Humans, Mutation, Oncogenes, Serine, Proto-Oncogene Proteins p21(ras)
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