Inhibition of RAS function through targeting an allosteric regulatory site
Open accessAbstract
RAS GTPases are important mediators of oncogenesis in humans. However, pharmacological inhibition of RAS has proved challenging. Here we describe a functionally critical region, located outside the effector lobe of RAS, that can be targeted for inhibition. We developed NS1, a synthetic binding protein (monobody) that bound with high affinity to both GTP- and GDP-bound states of H-RAS and K-RAS but not N-RAS. NS1 potently inhibited growth factor signaling and oncogenic H-RAS- and K-RAS-mediated signaling and transformation but did not block oncogenic N-RAS, BRAF or MEK1. NS1 bound the α4-β6-α5 region of RAS, which disrupted RAS dimerization and nanoclustering and led to blocking of CRAF-BRAF heterodimerization and activation. These results establish the importance of the α4-β6-α5 interface in RAS-mediated signaling and define a previously unrecognized site in RAS for inhibiting RAS function.
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
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?
Designing PPI inhibitors to block the interaction of RAS and RAS effect factors represents a promising paradigm for modulating RAS function and provides new impetus for the discovery of related drugs.
“Designing PPI inhibitors to block the interaction of RAS and RAS effect factors represents a promising paradigm for modulating RAS function and provides new impetus for the discovery of related drugs.86,326–329”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [329]
The binding sites of NS-1 and HRAS are located in the α4, α5, and β6 regions of the RAS protein opposite the RAS/RAF interface.
“The binding sites of NS-1 and HRAS are located in the α4, α5, and β6 regions of the RAS protein opposite the RAS/RAF interface.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [329]
The researchers used monomeric protein libraries to find a monomeric protein, NS-1, that specifically binds to HRAS but not NRAS.
“The researchers used monomeric protein libraries to find a monomeric protein, NS-1, that specifically binds to HRAS but not NRAS.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [329]
Spencer-Smith et al. recently reported a novel allosteric inhibitor that targets protein interactions between RAS and RAF.
“Spencer-Smith et al. recently reported a novel allosteric inhibitor that targets protein interactions between RAS and RAF.329”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [329]
The binding of NS-1 can allosterically induce structural changes in the SW-I and SW-II domains, thus disrupting the interaction between RAS and effector proteins, including RAF.
“The binding of NS-1 can allosterically induces structural changes in the SW-I and SW-II domains, thus disrupting the interaction between RAS and effector proteins, including RAF.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [329]
Experiments in bladder cancer cells showed that NS-1 can inhibit endogenous mutated RAS signal and corresponding cell proliferation.
“Experiments in bladder cancer cells showed that NS-1 can inhibit endogenous mutated RAS signal and corresponding cell proliferation.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [329]
Electron microscopy, BRET assay, and immunoprecipitation assay all confirmed that the interaction between RAS and RAF was destroyed by NS-1.
“Electron microscopy, BRET assay, and immunoprecipitation assay all confirmed that the interaction between RAS and RAF was destroyed by NS-1.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [329]
Further cell experiments demonstrated that NS-1 could effectively inhibit the activation of MAPK signaling pathway downstream of the RAS protein in cells.
“Further cell experiments demonstrated that NS-1 could effectively inhibit the activation of MAPK signaling pathway downstream of the RAS protein in cells.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [329]
NS1 disrupts the self-binding of HRAS and KRAS by directly binding to the α4-α5 interface, reducing activation of downstream pathways and inhibiting cell proliferation.
“Without interfering with RAS localization and GTPase activity, NS1 disrupts the self-binding of HRAS and KRAS by directly binding to the α4–α5 interface, reducing the activation of downstream pathways and inhibiting cell proliferation [30, 63, 64].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [63]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
<i>Coot</i> : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571 · see citing works
<i>PHENIX</i> : a comprehensive Python-based system for macromolecular structure solution
Adams, P. D., Afonine, P. V., Bunkóczi, G., Chen, V. B., Davis, I. W., Echols, N., Headd, J. J., Hung, L.-W., Kapral, G. J., Grosse-Kunstleve, R. W., et al. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909052925 · Cited by 23,716 · see citing works
<i>Phaser</i> crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612 · see citing works
The PyMOL Molecular Graphics System
DeLano, W. L. (2002) · Medical Entomology and Zoology · Cited by 18,147 · see citing works
<i>MolProbity</i> : all-atom structure validation for macromolecular crystallography
Chen, V. B., Arendall, W. B., Headd, J. J., Keedy, D. A., Immormino, R. M., Kapral, G. J., Murray, L. W., Richardson, J. S., & Richardson, D. C. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909042073 · Cited by 14,115 · see citing works
Inference of macromolecular assemblies from crystalline state.
Krissinel, E., & Henrick, K. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.05.022 · Cited by 10,189 · see citing works
Rapid and efficient site-specific mutagenesis without phenotypic selection.
Kunkel, T. A. (1985) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.82.2.488 · Cited by 7,309 · see citing works
[19] Rapid and efficient site-specific mutagenesis without phenotypic selection
Kunkel, T. A., Roberts, J. D., & Zakour, R. A. (1987) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(87)54085-x · Cited by 5,341 · see citing works
K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions
Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A., & Shokat, K. M. (2013) · Nature · doi:10.1038/nature12796 · Cited by 2,557 · see citing works
Minor, W., Cymborowski, M., Otwinowski, Z., & Chruszcz, M. (2006) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444906019949 · Cited by 2,118 · see citing works
Drugging the undruggable RAS: Mission Possible?
Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J., & Der, C. J. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4389 · Cited by 1,997 · see citing works
The Ras-RasGAP Complex: Structural Basis for GTPase Activation and Its Loss in Oncogenic Ras Mutants
Scheffzek, K., Ahmadian, M. R., Kabsch, W., Wiesmüller, L., Lautwein, A., Schmitz, F., & Wittinghofer, A. (1997) · Science · doi:10.1126/science.277.5324.333 · Cited by 1,543 · see citing works
Ras oncogenes: split personalities
Karnoub, A. E., & Weinberg, R. A. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2438 · Cited by 1,467 · see citing works
Shape Complementarity at Protein/Protein Interfaces
Lawrence, M. C., & Colman, P. M. (1993) · Journal of Molecular Biology · doi:10.1006/jmbi.1993.1648 · Cited by 1,219 · see citing works
Shape complementarity at protein–protein interfaces
Norel, R., Lin, S. L., Wolfson, H. J., & Nussinov, R. (1994) · Biopolymers · doi:10.1002/bip.360340711 · Cited by 1,208 · see citing works
PAI, E. F., Krengel, U., Petsko, G. A., Goody, R. S., Kabsch, W., & Wittinghofer, A. (1990) · The EMBO Journal · doi:10.1002/j.1460-2075.1990.tb07409.x · Cited by 1,074 · see citing works
Human RAS Superfamily Proteins and Related GTPases
Colicelli, J. (2004) · Science s STKE · doi:10.1126/stke.2502004re13 · Cited by 837 · see citing works
The structural basis of the activation of Ras by Sos
Boriack-Sjodin, P. A., Margarit, S. M., Bar-Sagi, D., & Kuriyan, J. (1998) · Nature · doi:10.1038/28548 · Cited by 799 · see citing works
Direct visualization of Ras proteins in spatially distinct cell surface microdomains
Prior, I. A., Muncke, C., Parton, R. G., & Hancock, J. F. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200209091 · Cited by 735 · see citing works
Self-citationRas history: The saga continues
Cox, A. D., & Der, C. J. (2010) · Small GTPases · doi:10.4161/sgtp.1.1.12178 · Cited by 706 · see citing works
Ras signalling on the endoplasmic reticulum and the Golgi
Chiu, V. K., Bivona, T., Hach, A., Sajous, J. B., Silletti, J., Wiener, H., Johnson, R. L., Cox, A. D., & Philips, M. R. (2002) · Nature Cell Biology · doi:10.1038/ncb783 · Cited by 594 · see citing works
The fibronectin type III domain as a scaffold for novel binding proteins
Koide, A., Bailey, C. W., Huang, X., & Koide, S. (1998) · Journal of Molecular Biology · doi:10.1006/jmbi.1998.2238 · Cited by 585 · see citing works
Self-citationA dimerization-dependent mechanism drives RAF catalytic activation
Rajakulendran, T., Sahmi, M., Lefrançois, M., Sicheri, F., & Therrien, M. (2009) · Nature · doi:10.1038/nature08314 · Cited by 492 · see citing works
Self-citationDiscovery of Small Molecules that Bind to K‐Ras and Inhibit Sos‐Mediated Activation
Sun, Q., Burke, J. P., Phan, J., Burns, M. C., Olejniczak, E. T., Waterson, A. G., Lee, T., Rossanese, O. W., & Fesik, S. W. (2012) · Angewandte Chemie International Edition · doi:10.1002/anie.201201358 · Cited by 490 · see citing works
Margarit, S. M., Sondermann, H., Hall, B. E., Nagar, B., Hoelz, A., Pirruccello, M., Bar‐Sagi, D., & Kuriyan, J. (2003) · Cell · doi:10.1016/s0092-8674(03)00149-1 · Cited by 486 · see citing works
Ras Isoforms Vary in Their Ability to Activate Raf-1 and Phosphoinositide 3-Kinase
Yan, J., Roy, S., Apolloni, A., Lane, A., & Hancock, J. F. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.37.24052 · Cited by 477 · see citing works
Self-citationPlowman, S. J., Muncke, C., Parton, R. G., & Hancock, J. F. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0504114102 · Cited by 468 · see citing works
Self-citationInhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface
Zhang, X., Pickin, K. A., Bose, R., Jura, N., Cole, P. A., & Kuriyan, J. (2007) · Nature · doi:10.1038/nature05998 · Cited by 357 · see citing works
Membrane potential modulates plasma membrane phospholipid dynamics and K-Ras signaling
Zhou, Y., Wong, C., Cho, K.-J., van der Hoeven, D., Hong, L., Thakur, D. P., Luo, J., Babić, M., Zinsmaier, K. E., Zhu, M. X., et al. (2015) · Science · doi:10.1126/science.aaa5619 · Cited by 313 · see citing works
Self-citationTherapeutic Targeting of Oncogenic K‐Ras by a Covalent Catalytic Site Inhibitor
Lim, S. M., Westover, K. D., Ficarro, S. B., Harrison, R. A., Choi, H. G., Pacold, M. E., Carrasco, M., Hunter, J., Kim, N. D., Xie, T., et al. (2014) · Angewandte Chemie International Edition · doi:10.1002/anie.201307387 · Cited by 300 · see citing works
An orthosteric inhibitor of the Ras-Sos interaction
Patgiri, A., Yadav, K. K., Arora, P. S., & Bar‐Sagi, D. (2011) · Nature Chemical Biology · doi:10.1038/nchembio.612 · Cited by 294 · see citing works
Shima, F., Yoshikawa, Y., Ye, M., Araki, M., Matsumoto, S., Liao, J., Hu, L., Sugimoto, T., Ijiri, Y., Takeda, A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1217730110 · Cited by 293 · see citing works
Ras-GTP dimers activate the Mitogen-Activated Protein Kinase (MAPK) pathway
Nan, X., Tamgüney, T. M., Collisson, E. A., Lin, L.-J., Pitt, C., Galeas, J., Lewis, S., Gray, J. W., McCormick, F., & Chu, S. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1509123112 · Cited by 273 · see citing works
Vav2 Is an Activator of Cdc42, Rac1, and RhoA
Abe, K., Rossman, K. L., Liu, B., Ritola, K., Chiang, D. Y., Campbell, S. L., Burridge, K., & Der, C. J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.14.10141 · Cited by 262 · see citing works
Koide, A., Wojcik, J., Gilbreth, R. N., Hoey, R. J., & Koide, S. (2012) · Journal of Molecular Biology · doi:10.1016/j.jmb.2011.12.019 · Cited by 227 · see citing works
Self-citationAllosteric Effects of the Oncogenic RasQ61L Mutant on Raf-RBD
Fetics, S., Guterres, H., Kearney, B. M., Buhrman, G., Ma, B., Nussinov, R., & Mattos, C. (2015) · Structure · doi:10.1016/j.str.2014.12.017 · Cited by 225 · see citing works
Mazhab-Jafari, M. T., Marshall, C. B., Smith, M. J., Gasmi-Seabrook, G. M. C., Stathopulos, P. B., Inagaki, F., Kay, L. E., Neel, B. G., & Ikura, M. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1419895112 · Cited by 220 · see citing works
Self-citationGTP-Dependent K-Ras Dimerization
Muratcioglu, S., Chavan, T. S., Freed, B. C., Jang, H., Khavrutskii, L., Freed, R. N., Dyba, M. A., Stefanisko, K., Tarasov, S. G., Gursoy, A., et al. (2015) · Structure · doi:10.1016/j.str.2015.04.019 · Cited by 202 · see citing works
Effects of Raf Dimerization and Its Inhibition on Normal and Disease-Associated Raf Signaling
Freeman, A. K., Ritt, D. A., & Morrison, D. K. (2013) · Molecular Cell · doi:10.1016/j.molcel.2012.12.018 · Cited by 201 · see citing works
Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange
Burns, M. C., Sun, Q., Daniels, R. N., Camper, D., Kennedy, J. P., Phan, J., Olejniczak, E. T., Lee, T., Waterson, A. G., Rossanese, O. W., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1315798111 · Cited by 199 · see citing works
A novel switch region regulates H‐ras membrane orientation and signal output
Abankwa, D., Hanzal‐Bayer, M., Ariotti, N., Plowman, S. J., Gorfe, A. A., Parton, R. G., McCammon, J. A., & Hancock, J. F. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.10 · Cited by 199 · see citing works
Self-citationProtorP: a protein–protein interaction analysis server
Reynolds, C. R., Damerell, D., & Jones, S. (2008) · Bioinformatics · doi:10.1093/bioinformatics/btn584 · Cited by 185 · see citing works
Inhibitors that stabilize a closed RAF kinase domain conformation induce dimerization
Lavoie, H., Thevakumaran, N., Gavory, G., Li, J. J., Padeganeh, A., Guiral, S., Duchaine, J., Mao, D. Y. L., Bouvier, M., Sicheri, F., et al. (2013) · Nature Chemical Biology · doi:10.1038/nchembio.1257 · Cited by 176 · see citing works
Self-citationThe structural basis for the transition from Ras-GTP to Ras-GDP
Hall, B. E., Bar‐Sagi, D., & Nassar, N. N. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.192453199 · Cited by 164 · see citing works
Nan, X., Collisson, E. A., Lewis, S., Huang, J., Tamgüney, T., Liphardt, J., McCormick, F. P., Gray, J. W., & Chu, S. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1318188110 · Cited by 159 · see citing works
Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices
Leshchiner, E. S., Parkhitko, A. A., Bird, G. H., Luccarelli, J., Bellairs, J. A., Escudero, S., Opoku-Nsiah, K., Godes, M., Perrimon, N., & Walensky, L. D. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1413185112 · Cited by 159 · see citing works
Formation of the Ras Dimer Is Essential for Raf-1 Activation
Inouye, K., Mizutani, S., Koide, H., & Kaziro, Y. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.6.3737 · Cited by 154 · see citing works
Feramisco, J. R., Clark, R., Wong, G., Arnheim, N., Milley, R. J., & McCormick, F. P. (1985) · Nature · doi:10.1038/314639a0 · Cited by 152 · see citing works
N-Ras Forms Dimers at POPC Membranes
Güldenhaupt, J., Rudack, T., Bachler, P. S., Mann, D., Triola, G., Waldmann, H., Kötting, C., & Gerwert, K. B. (2012) · Biophysical Journal · doi:10.1016/j.bpj.2012.08.043 · Cited by 148 · see citing works
Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes
Herrero, A., Pinto, A., Colón‐Bolea, P., Casar, B., Jones, M., Agudo‐Ibáñez, L., Vidal, R., Tenbaum, S. P., Nuciforo, P. G., Valdizán, E. M., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.07.001 · Cited by 148 · see citing works
Signal Integration by Lipid-Mediated Spatial Cross Talk between Ras Nanoclusters
Zhou, Y., Hong, L., Rodkey, T. L., Ariotti, N., Parton, R. G., & Hancock, J. F. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01227-13 · Cited by 133 · see citing works
Self-citationElectrostatic Interactions Positively Regulate K-Ras Nanocluster Formation and Function
Plowman, S. J., Ariotti, N., Goodall, A., Parton, R. G., & Hancock, J. F. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.00050-08 · Cited by 108 · see citing works
Self-citationSha, F., Akçok, E. B. G., Georgeon, S., Koide, A., Yasui, N., Koide, S., & Hantschel, O. D. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1303640110 · Cited by 104 · see citing works
Self-citationNonradioactive determination of Ras-GTP levels using activated ras interaction assay
Taylor, S. J., Resnick, R. J., & Shalloway, D. I. (2001) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(01)33067-7 · Cited by 91 · see citing works
Target-Binding Proteins Based on the 10th Human Fibronectin Type III Domain (10Fn3)
Koide, S., Koide, A., & Lipovšek, D. (2012) · Methods in Enzymology · doi:10.1016/b978-0-12-396962-0.00006-9 · Cited by 84 · see citing works
Self-citationInhibition of Ras–effector interactions by cyclic peptides
Wú, X., Upadhyaya, P., Villalona-Calero, M. A., Briesewitz, R., & Pei, D. (2012) · MedChemComm · doi:10.1039/c2md20329d · Cited by 69 · see citing works
Observing Cell Surface Signaling Domains Using Electron Microscopy
Prior, I. A., Parton, R. G., & Hancock, J. F. (2003) · Science s STKE · doi:10.1126/stke.2003.177.pl9 · Cited by 68 · see citing works
Self-citationGilbreth, R. N., Truong, K., Madu, I. G., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102294108 · Cited by 61 · see citing works
Oligomeric structure of p21 ras proteins as determined by radiation inactivation.
Santos, E., Nebreda, Á. R., Bryan, T., et al. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)81595-8 · Cited by 51 · see citing works
The Ras G Domain Lacks the Intrinsic Propensity to Form Dimers
Kovrigina, E. A., Galiakhmetov, A. R., & Kovrigin, E. L. (2015) · Biophysical Journal · doi:10.1016/j.bpj.2015.07.020 · Cited by 39 · see citing works
A novel assay for the measurement of Raf-1 kinase activity
Bondzi, C., Grant, S., & Krystal, G. W. (2000) · Oncogene · doi:10.1038/sj.onc.1203862 · Cited by 30 · see citing works
Wong, K. A., Russo, A., Wang, X., Chen, Y.-J., Lavie, A., & O’Bryan, J. P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0045360 · Cited by 23 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
RAS Proteins and Their Regulators in Human Disease
Simanshu, D. K., Nissley, D. V., & McCormick, F. (2017) · Cell · doi:10.1016/j.cell.2017.06.009 · Cited by 1,943 · see citing works
RAS-targeted therapies: is the undruggable drugged?
Moore, A. R., Rosenberg, S. C., McCormick, F., & Malek, S. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0068-6 · Cited by 1,103 · see citing works
Therapeutic strategies to target RAS-mutant cancers
Ryan, M. B., & Corcoran, R. B. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-018-0105-0 · Cited by 420 · see citing works
Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS
Ambrogio, C., Köhler, J., Zhou, Z.-W., Wang, H., Paranal, R., Li, J., Capelletti, M., Caffarra, C., Li, S., Lv, Q., et al. (2018) · Cell · doi:10.1016/j.cell.2017.12.020 · Cited by 270 · see citing works
Targeting KRAS mutant cancers: from druggable therapy to drug resistance
Zhu, C., Guan, X., Zhang, X., Luan, X., Song, Z., Cheng, X., Zhang, W., & Qin, J.-J. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01629-2 · Cited by 231 · see citing works
Pharmacological targeting of RAS: recent success with direct inhibitors
O’Bryan, J. P. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2018.10.021 · Cited by 153 · see citing works
Self-citationChemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S)
Zhang, Z., Guiley, K. Z., & Shokat, K. M. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-01065-9 · Cited by 153 · see citing works
A potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS
Bery, N., Miller, A., & Rabbitts, T. (2020) · Nature Communications · doi:10.1038/s41467-020-17022-w · Cited by 132 · see citing works
GTP-State-Selective Cyclic Peptide Ligands of K-Ras(G12D) Block Its Interaction with Raf
Zhang, Z., Gao, R., Hu, Q., Peacock, H., Peacock, D. M., Dai, S., Shokat, K. M., & Suga, H. (2020) · ACS Central Science · doi:10.1021/acscentsci.0c00514 · Cited by 124 · see citing works
Ni, D., Lu, S., & Zhang, J. (2019) · Medicinal Research Reviews · doi:10.1002/med.21585 · Cited by 116 · see citing works
KRAS-specific inhibition using a DARPin binding to a site in the allosteric lobe
Bery, N., Legg, S., Debreczeni, J., Breed, J., Embrey, K., Stubbs, C., Kolasinska-Zwierz, P., Barrett, N., Marwood, R., Watson, J., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10419-2 · Cited by 97 · see citing works
Advances in targeted degradation of endogenous proteins
Röth, S., Fulcher, L. J., & Sapkota, G. P. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03112-6 · Cited by 92 · see citing works
Fang, Z., Marshall, C. B., Nishikawa, T., Gossert, A. D., Jansen, J. M., Jahnke, W., & Ikura, M. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2018.07.009 · Cited by 86 · see citing works
Self-citationDiscovery of High-Affinity Noncovalent Allosteric KRAS Inhibitors That Disrupt Effector Binding
McCarthy, M. J., Pagba, C. V., Prakash, P., Naji, A. K., van der Hoeven, D., Liang, H., Gupta, A. K., Zhou, Y., Cho, K.-J., Hancock, J. F., et al. (2019) · ACS Omega · doi:10.1021/acsomega.8b03308 · Cited by 90 · see citing works
Self-citationLim, S., Khoo, R., Juang, Y.-C., Gopal, P., Zhang, H., Yeo, C., Peh, K. M., Teo, J., Ng, S., Henry, B., et al. (2021) · ACS Central Science · doi:10.1021/acscentsci.0c01337 · Cited by 80 · see citing works
Mo, S. P., Coulson, J. M., & Prior, I. A. (2018) · Biochemical Society Transactions · doi:10.1042/bst20180173 · Cited by 85 · see citing works
RAS, wanted dead or alive: Advances in targeting RAS mutant cancers
Stalnecker, C. A., & Der, C. J. (2020) · Science Signaling · doi:10.1126/scisignal.aay6013 · Cited by 90 · see citing works
Sakamoto, K., Masutani, T., & Hirokawa, T. (2020) · Scientific Reports · doi:10.1038/s41598-020-78712-5 · Cited by 85 · see citing works
Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges
Tang, D., Kroemer, G., & Kang, R. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01422-7 · Cited by 80 · see citing works
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 · see citing works
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 · see citing works
K-Ras prenylation as a potential anticancer target
Baranyi, M., Buday, L., & Hegedűs, B. (2020) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09902-w · Cited by 62 · see citing works
Zhou, Z.-W., Ambrogio, C., Bera, A. K., Li, Q., Li, X.-X., Li, L., Son, J., Gondi, S., Li, J., Campbell, E., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-20-0448 · Cited by 60 · see citing works
Targeting the α4–α5 dimerization interface of K-RAS inhibits tumor formation in vivo
Khan, I., Spencer-Smith, R., & O’Bryan, J. P. (2019) · Oncogene · doi:10.1038/s41388-018-0636-y · Cited by 54 · see citing works
Self-citationThe role of wild-type RAS in oncogenic RAS transformation
Sheffels, E., & Kortum, R. L. (2021) · Genes · doi:10.3390/genes12050662 · Cited by 42 · see citing works
“These data corroborated findings that mutant KRAS may act as a dimer, requiring both monomers to be activated to achieve full downstream effector engagement [46,47].”
BackgroundEfforts to Develop KRAS Inhibitors
Holderfield, M. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031864 · Cited by 43 · see citing works
Data from Delineating the RAS Conformational Landscape
Parker, M. I., Meyer, J. E., Golemis, E. A., & Dunbrack (2023) · doi:10.1158/0008-5472.c.6513960
- Authors
- Spencer-Smith, R., Koide, A., Zhou, Y., Eguchi, R. R., Sha, F., Gajwani, P., Santana, D., Gupta, A., Jacobs, M., Herrero-Garcia, E., Cobbert, J., Lavoie, H., Smith, M., Rajakulendran, T., Dowdell, E., Okur, M. N., Dementieva, I., Sicheri, F., Therrien, M., Hancock, J. F., Ikura, M., Koide, S., & O'Bryan, J. P.
- Affiliations
- University of Illinois Chicago (US)
- University of Chicago (US)
- Institute for Research in Immunology and Cancer (CA)
- University of Toronto (CA)
- Corresponding author
- Koide, Shohei
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2016-11-07
- Volume
- 13
- Issue
- 1
- Pages
- 62-68
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC5193369
- OpenAlex
- W2548573003
- Cited by
- 283
- References
- 62
- Citations by year
- 2026: 11 · 2025: 19 · 2024: 25 · 2023: 26 · 2022: 24 · 2021: 47 · 2020: 45 · 2019: 33 · 2018: 25 · 2017: 25 · 2016: 1
- FWCI
- 14.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX002095)
- National Cancer Institute (R21CA201717, F31CA192822, R01CA116708, R01CA212608)
- National Institute of General Medical Sciences (R01GM090324)
- 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 › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- Ras GTPase, allosteric inhibition, monobody, H-Ras, KRAS, NRAS, oncogenic transformation, growth factor signaling
- MeSH terms
- Allosteric Site, Animals, Antibodies, Monoclonal, Cells, Cultured, Chlorocebus aethiops, Humans, ras Proteins, COS Cells, NIH 3T3 Cells, Mice, HEK293 Cells
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
