Pharmacological targeting of RAS: recent success with direct inhibitors
Open accessAbstract
RAS has long been viewed as undruggable due to its lack of deep pockets for binding of small molecule inhibitors. However, recent successes in the development of direct RAS inhibitors suggest that the goal of pharmacological inhibition of RAS in patients may soon be realized. This review will discuss the role of RAS in cancer, the approaches used to develop direct RAS inhibitors, and highlight recent successes in the development of novel RAS inhibitory compounds that target different aspects of RAS biochemistry. In particular, this review will discuss the different properties of RAS that have been targeted by various inhibitors including membrane localization, the different activation states of RAS, effector binding, and nucleotide exchange. In addition, this review will highlight the recent success with mutation-specific inhibitors that exploit the unique biochemistry of the RAS(G12C) mutant. Although this mutation in KRAS accounts for 11% of all KRAS mutations in cancer, it is the most prominent KRAS mutant in lung cancer suggesting that G12C-specific inhibitors may provide a new approach for treating the subset of lung cancer patients harboring this mutant allele. Finally, this review will discuss the involvement of dimerization in RAS function and highlight new approaches to inhibit RAS by specifically interfering with RAS:RAS interaction.
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KRAS mutation is the most frequently observed RAS gene mutation, accounting for 83% of all RAS mutations in human cancers.
“Among different RAS gene mutations, KRAS mutation is the most frequently observed, accounting for 83% of all RAS mutations in human cancers.8,36”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [36]
Glycine codon 12 (G12) and G13 mutations represent 81.5% and 14% of all KRAS mutations, respectively, while mutations in other positions of KRAS are rare.
“Glycine codon 12 (G12) and G13 mutations represent 81.5% and 14% of all KRAS mutations, respectively, while the mutations in other positions of KRAS gene are rare.8,36”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [36]
KRASG12C inhibitors do not affect RAS signalling in non-malignant cells and theoretically carry a low risk of on-target, off-tumour toxicity.
“Accordingly, inhibitors of this type are KRASG12C specific; therefore, they do not affect RAS signalling in non-malignant cells65,70–72 and, at least theoretically, have a low risk of on-target, off-tumour toxicities.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [71]
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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
Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome
Eriksson, M., Brown, W. T., Gordon, L. B., Glynn, M. W., Singer, J. I., Scott, L. J., Erdos, M. R., Robbins, C. M., Moses, T. Y., Berglund, P., et al. (2003) · Nature · doi:10.1038/nature01629 · Cited by 2,217 · see citing works
Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism
Ying, H., Kimmelman, A. C., Lyssiotis, C. A., Hua, S., Chu, G. C., Fletcher-Sananikone, E., Locasale, J. W., Son, J., Zhang, H., Coloff, J. L., et al. (2012) · Cell · doi:10.1016/j.cell.2012.01.058 · Cited by 2,043 · see citing works
Mammalian Ras interacts directly with the serine/threonine kinase Raf.
Vojtek, A., Hollenberg, S., & Cooper, J. A. (1993) · Cell · doi:10.1016/0092-8674(93)90307-c · Cited by 1,971 · see citing works
COSMIC: somatic cancer genetics at high-resolution
Forbes, S. A., Beare, D., Boutselakis, H., Bamford, S., Bindal, N., Tate, J., Cole, C. G., Ward, S., Dawson, E., Ponting, L., et al. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkw1121 · Cited by 1,922 · see citing works
Lamin A Truncation in Hutchinson-Gilford Progeria
Sandre‐Giovannoli, A. D., Bernard, R., Cau, P., Navarro, C. L., Amiel, J., Boccaccio, I., Lyonnet, S., Stewart, C. L., Münnich, A., Merrer, M. F. L., et al. (2003) · Science · doi:10.1126/science.1084125 · Cited by 1,472 · see citing works
Kinase-targeted cancer therapies: progress, challenges and future directions
Bhullar, K. S., Orrego-Lagarón, N., McGowan, E. M., Parmar, I., Jha, A., Hubbard, B. P., & Rupasinghe, H. P. V. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0804-2 · Cited by 1,260 · see citing works
Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor
Janes, M. R., Zhang, J., Li, L.-S., Hansen, R., Peters, U., Guo, X., Chen, Y., Babbar, A., Firdaus, S. J., Darjania, L., et al. (2018) · Cell · doi:10.1016/j.cell.2018.01.006 · Cited by 1,172 · cited 2× · see citing works
“The most promising thus far appear to be the SII-P inhibitors targeting KRAS(G12C) mutants [53].”
BackgroundStable suppression of tumorigenicity by virus-mediated RNA interference
Brummelkamp, T. R., Bernards, R., & Agami, R. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00122-8 · Cited by 1,137 · 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
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 · see citing works
Hancock, J. F., Paterson, H., & Marshall, C. J. (1990) · Cell · doi:10.1016/0092-8674(90)90294-o · Cited by 1,042 · see citing works
RAS isoforms and mutations in cancer at a glance
Hobbs, G. A., Der, C. J., & Rossman, K. L. (2016) · Journal of Cell Science · doi:10.1242/jcs.182873 · Cited by 973 · see citing works
Complexes of Ras⋅GTP with Raf-1 and Mitogen-Activated Protein Kinase Kinase
Moodie, S. A., Willumsen, B. M., Weber, M. J., & Wolfman, A. (1993) · Science · doi:10.1126/science.8503013 · Cited by 968 · see citing works
Essential role for oncogenic Ras in tumour maintenance
Chin, L., Tam, A., Pomerantz, J. H., Wong, M., Holash, J., Bardeesy, N., Shen, Q., O'Hagan, R., Pantginis, J., Zhou, H., et al. (1999) · Nature · doi:10.1038/22788 · Cited by 928 · see citing works
K- and N-Ras Are Geranylgeranylated in Cells Treated with Farnesyl Protein Transferase Inhibitors
Whyte, D. B., Kirschmeier, P., Hockenberry, T. N., Nunez-Oliva, I., James, L., Catino, J. J., Bishop, W. R., & Pai, J.-K. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.22.14459 · Cited by 884 · see citing works
PAI, E. F., Kabsch, W., Krengel, U., Holmes, K. C., John, J., & Wittinghofer, A. (1989) · Nature · doi:10.1038/341209a0 · Cited by 879 · see citing works
Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1
Zhang, X., Settleman, J. E., Kyriakis, J. M., Takeuchi-Suzuki, E., Elledge, S. J., Marshall, M. S., Bruder, J. T., Rapp, U. R., & Avruch, J. (1993) · Nature · doi:10.1038/364308a0 · Cited by 859 · see citing works
Requirement for ras proto-oncogene function during serum-stimulated growth of NIH 3T3 cells
Mulcahy, L. S., Smith, M. R., & Stacey, D. W. (1985) · Nature · doi:10.1038/313241a0 · Cited by 842 · see citing works
Singh, A., Greninger, P., Rhodes, D., Koopman, L., Violette, S., Bardeesy, N., & Settleman, J. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.03.022 · Cited by 841 · see citing works
Inhibition of purified p21 farnesyl:protein transferase by Cys-AAX tetrapeptides
Reiss, Y., Goldstein, J. L., Seabra, M. C., Casey, P. J., & Brown, M. S. (1990) · Cell · doi:10.1016/0092-8674(90)90242-7 · Cited by 817 · see citing works
Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations
Hunter, J. C., Manandhar, A., Carrasco, M. A., Gurbani, D., Gondi, S., & Westover, K. D. (2015) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-15-0203 · Cited by 786 · see citing works
Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state
Patricelli, M. P., Janes, M. R., Li, L.-S., Hansen, R., Peters, U., Kessler, L. V., Chen, Y., Kucharski, J. M., Feng, J., Ely, T., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1105 · Cited by 759 · see citing works
Phenotype and Course of Hutchinson–Gilford Progeria Syndrome
Merideth, M. A., Gordon, L. B., Clauss, S. B., Sachdev, V., Smith, A. C. M., Perry, M. B., Brewer, C. C., Zalewski, C. K., Kim, H. J., Solomon, B. I., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0706898 · Cited by 740 · 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
Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro
Warne, P. H., Vician, P. R., & Downward, J. (1993) · Nature · doi:10.1038/364352a0 · Cited by 729 · see citing works
Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism
Lito, P., Solomon, M., Li, L.-S., Hansen, R., & Rosen, N. (2016) · Science · doi:10.1126/science.aad6204 · Cited by 691 · see citing works
Complex formation between RAS and RAF and other protein kinases.
Aelst, L. V., Barr, M. M., Marcus, S., Polverino, A. J., & Wigler, M. H. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.13.6213 · Cited by 623 · see citing works
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 · see citing works
Targeting protein prenylation for cancer therapy
Berndt, N., Hamilton, A. D., & Sebti, S. M. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3151 · Cited by 614 · see citing works
Haigis, K. M., Kendall, K. R., Wang, Y., Cheung, A., Haigis, M. C., Glickman, J. N., Niwa-Kawakita, M., Sweet-Cordero, A., Sebolt-Leopold, J., Shannon, K. M., et al. (2008) · Nature Genetics · doi:10.1038/ng.115 · Cited by 610 · see citing works
Crystal Structure and Functional Analysis of Ras Binding to Its Effector Phosphoinositide 3-Kinase γ
Pacold, M. E., Suire, S., Perišić, O., Lara‐González, S., Davis, C. T., Walker, E. H., Hawkins, P. T., Stephens, L., Eccleston, J. F., & Williams, R. L. (2000) · Cell · doi:10.1016/s0092-8674(00)00196-3 · Cited by 603 · see citing works
Small molecule inhibition of the KRAS–PDEδ interaction impairs oncogenic KRAS signalling
Zimmermann, G., Papke, B., Ismail, S., Vartak, N., Chandra, A., Hoffmann, M., Hahn, S. A., Triola, G., Wittinghofer, A., Bastiaens, P. I. H., et al. (2013) · Nature · doi:10.1038/nature12205 · Cited by 596 · see citing works
Fisher, G. H., Wellen, S. L., Klimstra, D., Lenczowski, J. M., Tichelaar, J. W., Lizak, M. J., Whitsett, J. A., Koretsky, A., & Varmus, H. E. (2001) · Genes & Development · doi:10.1101/gad.947701 · Cited by 582 · see citing works
GTP-dependent segregation of H-ras from lipid rafts is required for biological activity
Prior, I. A., Harding, A. S., Yan, J., Sluimer, J. C., Parton, R. G., & Hancock, J. F. (2001) · Nature Cell Biology · doi:10.1038/35070050 · Cited by 513 · see citing works
A 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
Discovery 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
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
Plowman, 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
End, D. W., Smets, G., Todd, A. V., Applegate, T. L., Fuery, C. J., Angibaud, P., Venet, M., Sanz, G., Poignet, H., Skrzat, S., et al. (2001) · PubMed · doi:10.7270/q20c4t2r · Cited by 461 · see citing works
Konstantinopoulos, P. A., Karamouzis, M. V., & Papavassiliou, A. G. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2221 · Cited by 451 · see citing works
Regulation and Role of Raf-1/B-Raf Heterodimerization
Rushworth, L. K., Hindley, A. D., O’Neill, E. E., & Kölch, W. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.6.2262-2272.2006 · Cited by 419 · see citing works
Gordon, L. B., Kleinman, M. E., Miller, D. T., Neuberg, D. S., Giobbie‐Hurder, A., Gerhard‐Herman, M. D., Smoot, L. B., Gordon, C. M., Cleveland, R., Snyder, B. D., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1202529109 · Cited by 376 · see citing works
KRAS Alleles: The Devil Is in the Detail
Haigis, K. M. (2017) · Trends in Cancer · doi:10.1016/j.trecan.2017.08.006 · Cited by 373 · see citing works
Direct Demonstration of Geranylgeranylation and Farnesylation of Ki-Ras in Vivo
Rowell, C. A., Kowalczyk, J. J., Lewis, M. D., & Garcia, A. M. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.22.14093 · Cited by 368 · see citing works
Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma
Kwong, L. N., Costello, J. C., Liu, H., Jiang, S., Helms, T. L., Langsdorf, A. E., Jakubosky, D., Genovese, G., Muller, F. L., Jeong, J. H., et al. (2012) · Nature Medicine · doi:10.1038/nm.2941 · Cited by 358 · see citing works
Chandra, A., Grecco, H. E., Pisupati, V., Perera, D., Cassidy, L., Skoulidis, F., Ismail, S. A., Hedberg, C., Hanzal-Bayer, M., Venkitaraman, A. R., et al. (2012) · Nature Cell Biology · doi:10.1038/ncb2394 · Cited by 325 · see citing works
A Protein Farnesyltransferase Inhibitor Ameliorates Disease in a Mouse Model of Progeria
Fong, L. G., Frost, D. J., Meta, M. D., Qiao, X., Yang, S. H., Coffinier, C., & Young, S. G. (2006) · Science · doi:10.1126/science.1124875 · Cited by 315 · see citing works
Active Ras induces heterodimerization of cRaf and BRaf.
Weber, C., Slupsky, J. R., Kalmes, H. A., & Rapp, U. R. (2001) · PubMed · Cited by 312 · 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
James, G. L., Goldstein, J. L., & Brown, M. S. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.11.6221 · Cited by 290 · see citing works
Voice, J. K., Klemke, R. L., Le, A., & Jackson, J. H. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.24.17164 · Cited by 288 · see citing works
Inhibition of RAS function through targeting an allosteric regulatory site
Spencer-Smith, R., Koide, A., Zhou, Y., Eguchi, R. R., Sha, F., Gajwani, P., Santana, D., Gupta, A., Jacobs, M., Herrero-Garcia, E., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2231 · Cited by 283 · see citing works
Self-citationLane, K. T., & Beese, L. S. (2006) · Journal of Lipid Research · doi:10.1194/jlr.r600002-jlr200 · Cited by 281 · 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
Functional Specificity of Ras Isoforms: So Similar but So Different
Castellano, E., & Santos, E. (2011) · Genes & Cancer · doi:10.1177/1947601911408081 · Cited by 273 · see citing works
Multivalent Small-Molecule Pan-RAS Inhibitors
Welsch, M., Kaplan, A. R., Chambers, J. M., Stokes, M. E., Bos, P. H., Zask, A., Zhang, Y., Sánchez-Martín, M., Badgley, M. A., Huang, C., et al. (2017) · Cell · doi:10.1016/j.cell.2017.02.006 · Cited by 273 · 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
Kraulis, P. J., Domaille, P. J., Campbell, S. L., Aken, T. V., & Laue, E. D. (1994) · Biochemistry · doi:10.1021/bi00178a008 · Cited by 267 · see citing works
Hayes, T. K., Neel, N. F., Hu, C., Gautam, P., Chénard, M., Long, B. J., Aziz, M., Kassner, M., Bryant, K. L., Pierobon, M., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.11.011 · Cited by 266 · see citing works
NMR-based functional profiling of RASopathies and oncogenic RAS mutations
Smith, M. J., Neel, B. G., & Ikura, M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1218173110 · Cited by 257 · see citing works
Schmick, M., Vartak, N., Papke, B., Kovacevic, M., Truxius, D. C., Rossmannek, L., & Bastiaens, P. I. H. (2014) · Cell · doi:10.1016/j.cell.2014.02.051 · Cited by 243 · see citing works
Ras nanoclusters: Versatile lipid-based signaling platforms
Zhou, Y., & Hancock, J. F. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.09.008 · Cited by 224 · see citing works
Ras membrane orientation and nanodomain localization generate isoform diversity
Abankwa, D., Gorfe, A. A., Inder, K. L., & Hancock, J. F. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903907107 · Cited by 223 · see citing works
Gordon, L. B., Shappell, H. M., Massaro, J., D’Agostino, R. B., Brazier, J. F., Campbell, S. E., Kleinman, M. E., & Kieran, M. W. (2018) · JAMA · doi:10.1001/jama.2018.3264 · Cited by 223 · see citing works
Sulfone metabolite of sulindac inhibits mammary carcinogenesis.
Thompson, H. J., Jiang, C., Lü, J., Mehta, R. G., Piazza, G. A., Paranka, N. S., Pamukcu, R., & Ahnen, D. J. (1997) · PubMed · Cited by 209 · 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
Lim, K., & Counter, C. M. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.10.014 · Cited by 191 · see citing works
Metastatic pancreatic cancer is dependent on oncogenic Kras in mice
Collins, M. A., Brisset, J.-C., Zhang, Y., Bednar, F., Pierre, J., Heist, K. A., Galbán, C. J., Galbán, S., & di Magliano, M. P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049707 · Cited by 178 · see citing works
Novel Allosteric Sites on Ras for Lead Generation
Grant, B. J., Lukman, S., Hocker, H. J., Sayyah, J., Brown, J. H., McCammon, J. A., & Gorfe, A. A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0025711 · Cited by 178 · see citing works
Koide, H., Satoh, T., Nakafuku, M., & Kaziro, Y. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.18.8683 · Cited by 176 · see citing works
Structural basis of recognition of farnesylated and methylated KRAS4b by PDEδ
Dharmaiah, S., Bindu, L. K., Tran, T. H., Gillette, W., Frank, P. H., Ghirlando, R., Nissley, D. V., Esposito, D., McCormick, F. P., Stephen, A. G., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1615316113 · Cited by 176 · see citing works
Monobodies and other synthetic binding proteins for expanding protein science
Sha, F., Salzman, G., Gupta, A., & Koide, S. (2017) · Protein Science · doi:10.1002/pro.3148 · Cited by 165 · see citing works
Identification of pyrazolopyridazinones as PDEδ inhibitors
Papke, B., Murarka, S., Vogel, H. A., Martín‐Gago, P., Kovačević, M., Truxius, D. C., Fansa, E. K., Ismail, S., Zimmermann, G., Heinelt, K. F., et al. (2016) · Nature Communications · doi:10.1038/ncomms11360 · Cited by 164 · see citing works
Regional Polysterism in the GTP-Bound Form of the Human c-Ha-Ras Protein,
Ito, Y., Yamasaki, K., Iwahara, J., Terada, T., Kamiya, A., Shirouzu, M., Muto, Y., Kawai, G., Yokoyama, S., Laue, E. D., et al. (1997) · Biochemistry · doi:10.1021/bi970296u · Cited by 163 · 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
Analysis of Binding Site Hot Spots on the Surface of Ras GTPase
Buhrman, G., O′Connor, C., Zerbe, B. S., Kearney, B. M., Napoleon, R. L., Kovrigina, E. A., Vajda, S., Kozakov, D., Kovrigin, E. L., & Mattos, C. (2011) · Journal of Molecular Biology · doi:10.1016/j.jmb.2011.09.011 · Cited by 158 · see citing works
A Biochemical Function for Ras—at Last
Hall, A. K. (1994) · Science · doi:10.1126/science.8197454 · Cited by 155 · 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
Tanaka, T. U., Williams, R. L., & Rabbitts, T. H. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601744 · Cited by 151 · see citing works
Three Separable Domains Regulate GTP-Dependent Association of H-ras with the Plasma Membrane
Rotblat, B., Prior, I. A., Muncke, C., Parton, R. G., Kloog, Y., Henis, Y. I., & Hancock, J. F. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.15.6799-6810.2004 · Cited by 150 · 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
Shin, S., Choi, D.-K., Jung, K., Bae, J., Kim, J., Park, S.-W., Song, K.-H., & Kim, Y. (2017) · Nature Communications · doi:10.1038/ncomms15090 · Cited by 144 · see citing works
Kato‐Stankiewicz, J., Hakimi, I., Zhi, G., Zhang, J., Serebriiskii, I. G., Guo, L., Edamatsu, H., Koide, H., Menon, S., Eckl, R. W., et al. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.222222699 · Cited by 143 · see citing works
Quevedo, C. E., Cruz-Migoni, A., Béry, N., Miller, A., Tanaka, T. U., Petch, D., Bataille, C. J. R., Lee, L. Y. W., Fallon, P. S., Tulmin, H., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05707-2 · Cited by 132 · see citing works
Sulindac sulfide inhibits Ras signaling
Herrmann, C., Block, C., Geisen, C., Haas, K., Weber, C. K., Winde, G., Möröy, T., & Müller, O. (1998) · Oncogene · doi:10.1038/sj.onc.1202085 · Cited by 129 · see citing works
Structural differences between a ras oncogene protein and the normal protein
Tong, L., de Vos, A. M., Milburn, M. V., Jancarik, J., Noguchi, S., Nishimura, S., Miura, K., Ohtsuka, E., & Kim, S. (1989) · Nature · doi:10.1038/337090a0 · Cited by 122 · see citing works
Thapar, R., Williams, J. G., & Campbell, S. L. (2004) · Journal of Molecular Biology · doi:10.1016/j.jmb.2004.08.106 · Cited by 119 · see citing works
Ras Binder Induces a Modified Switch-II Pocket in GTP and GDP States
Gentile, D. R., Rathinaswamy, M. K., Jenkins, M. L., Moss, S. M., Siempelkamp, B. D., Renslo, A. R., Burke, J. E., & Shokat, K. M. (2017) · Cell chemical biology · doi:10.1016/j.chembiol.2017.08.025 · Cited by 116 · see citing works
Tanaka, T. U., Lobato, M. N., & Rabbitts, T. H. (2003) · Journal of Molecular Biology · doi:10.1016/s0022-2836(03)00836-2 · Cited by 114 · see citing works
Stabilizing a Weak Binding State for Effectors in the Human Ras Protein by Cyclen Complexes
Rosnizeck, I. C., Gräf, T., Spoerner, M., Traenkle, J., Filchtinski, D., Herrmann, C., Gremer, L., Vetter, I. R., Wittinghofer, A., König, B., et al. (2010) · Angewandte Chemie International Edition · doi:10.1002/anie.200907002 · Cited by 107 · see citing works
Tong, L., Milburn, M. V., de Vos, A. M., & Kim, S. (1989) · Science · doi:10.1126/science.2665078 · Cited by 95 · see citing works
Njoroge, F. G., Taveras, A. G., Kelly, J. M., et al. (1998) · Journal of Medicinal Chemistry · doi:10.1021/jm980462b · Cited by 95 · see citing works
Spoerner, M., Nuehs, A., Ganser, P., Herrmann, C., Wittinghofer, A., & Kalbitzer, H. R. (2005) · Biochemistry · doi:10.1021/bi0488000 · Cited by 90 · see citing works
Martín‐Gago, P., Fansa, E. K., Klein, C. H., Murarka, S., Janning, P., Schürmann, M., Metz, M., Ismail, S., Schultz‐Fademrecht, C., Baumann, M., et al. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201610957 · Cited by 89 · see citing works
Direct inhibition of RAS: Quest for the Holy Grail?
Spencer-Smith, R., & O’Bryan, J. P. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.12.005 · Cited by 89 · see citing works
Self-citationFang, 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
New indene-derivatives with anti-proliferative properties
Karaguni, I., Glüsenkamp, K., Langerak, A., Geisen, C., Ullrich, V., Winde, G., Möröy, T., & Müller, O. (2002) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/s0960-894x(01)00839-3 · Cited by 83 · see citing works
Global Conformational Dynamics in Ras
O’Connor, C., & Kovrigin, E. L. (2008) · Biochemistry · doi:10.1021/bi801076c · Cited by 74 · see citing works
K-Ras4B Remains Monomeric on Membranes over a Wide Range of Surface Densities and Lipid Compositions
Chung, J. K., Lee, Y. K., Denson, J.-P., Gillette, W., Alvarez, S. A., Stephen, A. G., & Groves, J. T. (2018) · Biophysical Journal · doi:10.1016/j.bpj.2017.10.042 · Cited by 72 · see citing works
Tanaka, T. U., & Rabbitts, T. H. (2010) · Oncogene · doi:10.1038/onc.2010.346 · Cited by 62 · see citing works
A Cell-Permeable Inhibitor to Trap Gαq Proteins in the Empty Pocket Conformation
Schmitz, A.-L., Schrage, R., Gaffal, E., Charpentier, T. H., Wiest, J. M., Hiltensperger, G., Morschel, J., Hennen, S., Häußler, D., Horn, V., et al. (2014) · Chemistry & Biology · doi:10.1016/j.chembiol.2014.06.003 · Cited by 57 · see citing works
Béry, N., Cruz-Migoni, A., Bataille, C. J. R., Quevedo, C. E., Tulmin, H., Miller, A., Russell, A. J., Phillips, S. E. V., Carr, S. B., & Rabbitts, T. H. (2018) · eLife · doi:10.7554/elife.37122 · Cited by 56 · 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
A novel mechanism for the modulation of the Ras-effector interaction by small molecules
Spoerner, M., Gräf, T., König, B., & Kalbitzer, H. R. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.06.144 · Cited by 49 · see citing works
Lacal, J. C., & Aaronson, S. A. (1986) · Molecular and Cellular Biology · doi:10.1128/mcb.6.4.1002 · Cited by 47 · see citing works
Singh, A. K., Sowjanya, A. P., & Ramakrishna, G. (2005) · The FASEB Journal · doi:10.1096/fj.04-2584hyp · Cited by 47 · see citing works
González‐Pérez, V., Reiner, D. J., Alan, J. K., Mitchell, C. E., Edwards, L. J., Khazak, V., Der, C. J., & Cox, A. D. (2010) · Journal of Molecular Signaling · doi:10.1186/1750-2187-5-2 · Cited by 42 · see citing works
Novotny, C. J., Hamilton, G. L., McCormick, F. P., & Shokat, K. M. (2017) · ACS Chemical Biology · doi:10.1021/acschembio.7b00374 · Cited by 41 · 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
Skobeleva, N., Menon, S., Weber, L., et al. (2007) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-06-0602 · Cited by 29 · see citing works
Inhibition of prenylated KRAS in a lipid environment
Jansen, J. M., Wartchow, C. A., Jahnke, W., Fong, S. K., Tsang, T., Pfister, K. B., Zavorotinskaya, T., Bussiere, D. E., Cheng, J. M., Crawford, K. R., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0174706 · Cited by 29 · see citing works
Dementiev, A. (2012) · Protein Expression and Purification · doi:10.1016/j.pep.2012.04.021 · Cited by 22 · see citing works
Lu, Y., Sakamuri, S., Chen, Q., et al. (2004) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2004.05.048 · Cited by 19 · see citing works
Ke, H., Matsumoto, S., Murashima, Y., Taniguchi‐Tamura, H., Miyamoto, R., Yoshikawa, Y., Tsuda, C., Kumasaka, T., Mizohata, E., Edamatsu, H., et al. (2017) · FEBS Letters · doi:10.1002/1873-3468.12759 · Cited by 8 · see citing works
Studies on the iodination of aras protein and the detection ofras polymers
Chataway, T., & Barritt, G. J. (1994) · Molecular and Cellular Biochemistry · doi:10.1007/bf00926042 · Cited by 7 · see citing works
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Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma
Gillette, M. A., Satpathy, S., Cao, S., Dhanasekaran, S. M., Vasaikar, S. V., Krug, K., Petralia, F., Li, Y., Liang, W.-W., Reva, B., et al. (2020) · Cell · doi:10.1016/j.cell.2020.06.013 · Cited by 820 · see citing works
Dai, E., Han, L., Liu, J., Xie, Y., Kroemer, G., Klionsky, D. J., Zeh, H. J., Kang, R., Wang, J., & Tang, D. (2020) · Autophagy · doi:10.1080/15548627.2020.1714209 · Cited by 613 · see citing works
The current state of the art and future trends in RAS-targeted cancer therapies
Punekar, S. R., Velcheti, V., Neel, B. G., & Wong, K.-K. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00671-9 · Cited by 549 · see citing works
The current understanding on the impact of KRAS on colorectal cancer
Meng, M., Zhong, K., Jiang, T., Liu, Z., Kwan, H. Y., & Su, T. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111717 · Cited by 171 · see citing works
Chemical 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
Current therapy of KRAS-mutant lung cancer
Ghimessy, A., Radeczky, P., Laszlo, V., Hegedus, B., Renyi-Vamos, F., Fillinger, J., Klepetko, W., Lang, C., Dome, B., & Megyesfalvi, Z. (2020) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09903-9 · Cited by 115 · see citing works
Overcoming Resistance to Drugs Targeting KRAS Mutation
Jiao, D., & Yang, S. (2020) · The Innovation · doi:10.1016/j.xinn.2020.100035 · Cited by 61 · see citing works
Fragment-based drug discovery of triazole inhibitors to block PDEδ-RAS protein-protein interaction
Chen, D., Chen, Y., Lian, F., Chen, L., Li, Y., Cao, D., Wang, X., Chen, L., Li, J., Meng, T., et al. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.12.018 · Cited by 31 · see citing works
Ghimessy, Á. K., Gellert, Á., Schlegl, E., Hegedus, B., Raso, E., Barbai, T., Timar, J., Ostoros, G., Megyesfalvi, Z., Gieszer, B., et al. (2019) · Cancers · doi:10.3390/cancers11101514 · Cited by 27 · see citing works
Structure-based design of CDC42 effector interaction inhibitors for the treatment of cancer
Jahid, S., Ortega, J. A., Vuong, L. M., Acquistapace, I. M., Hachey, S. J., Flesher, J. L., La Serra, M. A., Brindani, N., La Sala, G., Manigrasso, J., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110641 · Cited by 21 · see citing works
- Authors
- O’Bryan, J. P.
- Affiliations
- Medical University of South Carolina (US)
- Corresponding author
- O’Bryan, John P.
- ORCID
- O’Bryan, John P.
- Venue
- Pharmacological Research
- Publisher
- Elsevier BV
- Published
- 2019-01
- Volume
- 139
- Pages
- 503-511
- ISSN
- 1043-6618 (ISSN-L)
- PMC
- PMC6360110
- OpenAlex
- W2897527318
- Cited by
- 153
- References
- 116
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 13 · 2023: 23 · 2022: 28 · 2021: 28 · 2020: 31 · 2019: 17 · 2018: 1
- FWCI
- 1.91
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Pharmacological Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- United States (US) Department of Veterans Affairs Biomedical Laboratory Research and Development Service and NIH awards (CA201717, CA212608)
- 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 › Melanoma and MAPK Pathways
- Keywords
- Ras, undruggable targets, KRAS G12C mutation, nucleotide exchange, effector binding, membrane localization, lung cancer, cancer therapy
- MeSH terms
- Animals, Antineoplastic Agents, Cell Membrane, Humans, Neoplasms, ras Proteins, Protein Multimerization
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