The DOI matches its Crossref record; 21 of the 21 references it cites were found in a registry or an index.
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Abstract
MDM2 binds the p53 tumor suppressor protein with high affinity and negatively modulates its transcriptional activity and stability. Overexpression of MDM2, found in many human tumors, effectively impairs p53 function. Inhibition of MDM2-p53 interaction can stabilize p53 and may offer a novel strategy for cancer therapy. Here, we identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes. These compounds bind MDM2 in the p53-binding pocket and activate the p53 pathway in cancer cells, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts in nude mice.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
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?
In the citing paper
“WB138 increases the levels of both p53 and MDM2, which is consistent with the activity of previous reports on MDM2 inhibitors[28,32–36].”
From Development of MDM2 degraders based on ligands derived from Ugi reactions: Lessons and discoveries (2021) · cites this paper as [32]
In the citing paper
“Nutlin-3a had the strongest activity, and its binding activity with MDM2 reached 90 nM.”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [20]
In the citing paper
“At 200 mg/kg, twice a day, 20 days after oral administration of Nutlin-3a, the tumor growth inhibition rate reached 90%, with no obvious side effects [20].”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [20]
In the citing paper
“Moreover, others have shown that inhibition of MDM2 binding to p53 or p73α appears to be more effective at promoting p53- and p73α-mediated apoptosis in cancer cells compared with normal cells.19,45”
From Combination therapy in a xenograft model of glioblastoma: Enhancement of the antitumor activity of temozolomide by an MDM2 antagonist (2017) · cites this paper as [45]
In the citing paper
“Nutlin-3a is a small molecule, which binds to the N-terminal hydrophobic pocket of Mdm2 and blocks protein-protein interactions (PPIs) between Mdm2 and p53 (10).”
From Potentiation of carboplatin-mediated DNA damage by the Mdm2 modulator Nutlin-3a in a humanized orthotopic breast-to-lung metastatic model (2015) · cites this paper as [10]
In the citing paper
“It has been reported that a consequence of Nutlin treatment is elevated Mdm2 protein levels, and this occurs in cells with or without p53 (6,8).”
From Pharmacologically increasing Mdm2 Inhibits DNA repair and cooperates with genotoxic agents to kill p53-inactivated ovarian cancer cells (2015) · cites this paper as [6]
In the citing paper
“Nutlin-3 is a small molecule inhibitor of Mdm2/p53 interaction that can induce apoptosis in cancer cells through activation of p53.”
From Pharmacologically increasing Mdm2 Inhibits DNA repair and cooperates with genotoxic agents to kill p53-inactivated ovarian cancer cells (2015) · cites this paper as [6]
In the citing paper
“Nonmalignant tissues tolerate inhibition of Mdm2, and no overt toxicity was observed in preclinical in vivo models.9,11”
From Mdm2 inhibitors synergize with topoisomerase II inhibitors to induce p53-independent pancreatic cancer cell death (2013) · cites this paper as [9]
In the citing paper
“For example, small molecule antagonism of the Mdm2–p53 interaction promotes p53-dependent tumor regression in murine models [102,103].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [103]
In the citing paper
“Small-molecule PPI antagonists that disrupt the p53–MDM2 interaction have been identified, including nutlin 3a96 and MI-219 (Ref. 97).”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [96]
In the citing paper
“To utilize MDM2 for the PROTAC system, the discovery of nutlins, small molecules that bind MDM2 at the p53 interaction interface, was a crucial step [66].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [66]
Citations
Cites
WAF1, a potential mediator of p53 tumor suppression
El-Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, K. W., & Vogelstein, B. (1993) · Cell · doi:10.1016/0092-8674(93)90500-p · Cited by 8,321
p53 Mutations in Human Cancers
Hollstein, M., Sidransky, D., Vogelstein, B., & Harris, C. C. (1991) · Science · doi:10.1126/science.1905840 · Cited by 8,018
p53, the cellular gatekeeper for growth and division
Levine, A. J. (1997) · Cell · doi:10.1016/s0092-8674(00)81871-1 · Cited by 7,693
Vogelstein, B., Lane, D., & Levine, A. J. (2000) · Nature · doi:10.1038/35042675 · Cited by 6,607
Requirement for p53 and p21 to Sustain G 2 Arrest After DNA Damage
Bunz, F., Dutriaux, A., Lengauer, C., Waldman, T., Zhou, S., Brown, J. P., Sedivy, J. M., Kinzler, K. W., & Vogelstein, B. (1998) · Science · doi:10.1126/science.282.5393.1497 · Cited by 2,803
Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain
Kussie, P. H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A. J., & Pavletich, N. P. (1996) · Science · doi:10.1126/science.274.5289.948 · Cited by 2,206
Amplification of a gene encoding a p53-associated protein in human sarcomas
Oliner, J. D., Kinzler, K. W., Meltzer, P. S., George, D. L., & Vogelstein, B. (1992) · Nature · doi:10.1038/358080a0 · Cited by 1,949
The p53-mdm-2 autoregulatory feedback loop.
Wu, X., Bayle, J. H., Olson, D., & Levine, A. J. (1993) · Genes & Development · doi:10.1101/gad.7.7a.1126 · Cited by 1,801
Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53
Oliner, J. D., Pietenpol, J. A., Thiagalingam, S., Gyuris, J., Kinzler, K. W., & Vogelstein, B. (1993) · Nature · doi:10.1038/362857a0 · Cited by 1,474
The MDM2 gene amplification database
Momand, J. (1998) · Nucleic Acids Research · doi:10.1093/nar/26.15.3453 · Cited by 982
Research works printed but not linked: 3
- D. Freedman, A. J. Levine, Cell. Mol. Life Sci.5, 96 (1999).
- R. Zhang, H. Wang, Methods Mol. Med.85, 205 (2003).
- L. T. Vassilevet al., Anticancer Drug Des.13, 359 (2001).
Cited by
Sorted by citations
Items 201–300 of 1,103
Peptide therapeutics: Targeting the undruggable space
Tsomaia, N. (2015) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2015.01.014 · Cited by 361
Targeting p53 for the treatment of cancer
Duffy, M. J., Synnott, N. C., O’Grady, S., & Crown, J. P. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.07.005 · Cited by 355
p53 — a Jack of all trades but master of none
Junttila, M. R., & Evan, G. I. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2728 · Cited by 368
The Mdm2–p53 relationship evolves: Mdm2 swings both ways as an oncogene and a tumor suppressor
Manfredi, J. J. (2010) · Genes & Development · doi:10.1101/gad.1941710 · Cited by 344
A Designed Inhibitor of p53 Aggregation Rescues p53 Tumor Suppression in Ovarian Carcinomas
Soragni, A., Janzen, D. M., Johnson, L. M., Lindgren, A. G., Thai-Quynh Nguyen, A., Tiourin, E., Soriaga, A. B., Lu, J., Jiang, L., Faull, K. F., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2015.12.002 · Cited by 341
Rational design of shepherdin, a novel anticancer agent
Plescia, J., Salz, W., Xia, F., Pennati, M., Zaffaroni, N., Daidone, M. G., Meli, M., Dohi, T., Fortugno, P., Nefedova, Y., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.03.035 · Cited by 342
Understanding eukaryotic linear motifs and their role in cell signaling and regulation
Diella, F. (2008) · Frontiers in bioscience · doi:10.2741/3175 · Cited by 349
Wang, S., Sun, W., Zhao, Y., McEachern, D., Meaux, I., Barrière, C., Stuckey, J. A., Meagher, J. L., Bai, L., Liu, L., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0799 · Cited by 328
SCF ubiquitin ligase-targeted therapies
Skaar, J. R., Pagan, J. K., & Pagano, M. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4432 · Cited by 344
Ward, C. C., Kleinman, J. I., Brittain, S. M., Lee, P. S., Chung, C. Y. S., Kim, K., Petri, Y., Thomas, J. R., Tallarico, J. A., McKenna, J. M., et al. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.8b01083 · Cited by 336
WD40 repeat domain proteins: a novel target class?
Schapira, M., Tyers, M., Torrent, M., & Arrowsmith, C. H. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.179 · Cited by 335
Tolia, N. H., Enemark, E. J., Sim, B. K. L., & Joshua‐Tor, L. (2005) · Cell · doi:10.1016/j.cell.2005.05.033 · Cited by 331
MDM4 is a key therapeutic target in cutaneous melanoma
Gembarska, A., Luciani, F., Fedele, C., Russell, E. A., Dewaele, M., Villar, S., Zwolinska, A., Haupt, S., de Lange, J., Yip, D., et al. (2012) · Nature Medicine · doi:10.1038/nm.2863 · Cited by 327
Degradation of proteins by PROTACs and other strategies
Wang, Y., Jiang, X., Feng, F., Liu, W., & Sun, H. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2019.08.001 · Cited by 335
The Role of p53 Signaling in Colorectal Cancer
Liebl, M. C., & Hofmann, T. G. (2021) · Cancers · doi:10.3390/cancers13092125 · Cited by 350
Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells
Colland, F., Formstecher, É., Jacq, X., Reverdy, C., Planquette, C., Conrath, S., Trouplin, V., Bianchi, J., Aushev, V. N., Camonis, J., et al. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-0097 · Cited by 329
Clinical Overview of MDM2/X-Targeted Therapies
Burgess, A., Chia, K. M., Haupt, S., Thomas, D., Haupt, Y., & Lim, E. (2016) · Frontiers in Oncology · doi:10.3389/fonc.2016.00007 · Cited by 315
Coordination and communication between the p53 and IGF-1–AKT–TOR signal transduction pathways
Levine, A. J., Feng, Z., Mak, T. W., You, H., & Jin, S. (2006) · Genes & Development · doi:10.1101/gad.1363206 · Cited by 321
Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells
Yang, Y., Ludwig, R. L., Jensen, J. P., Pierre, S. A., Medaglia, M. V., Davydov, I. V., Safiran, Y. J., Oberoi, P., Kenten, J. H., Phillips, A. C., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.04.029 · Cited by 327
Anderson, M. A., Deng, J., Seymour, J. F., Tam, C. S. L., Kim, S. Y., Fein, J. A., Yu, L., Brown, J. R., Westerman, D., Si, E. G., et al. (2016) · Blood · doi:10.1182/blood-2016-01-688796 · Cited by 317
Kong, N., Tao, W., Ling, X., Wang, J., Xiao, Y., Shi, S., Ji, X., Shajii, A., Gan, S. T., Kim, N. Y., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aaw1565 · Cited by 314
Self-citationHelical β-Peptide Inhibitors of the p53-hDM2 Interaction
Kritzer, J. A., Lear, J. D., Hodsdon, M. E., & Schepartz, A. (2004) · Journal of the American Chemical Society · doi:10.1021/ja031625a · Cited by 322
Chemistries of bifunctional PROTAC degraders
Cao, C., He, M., Wang, L., He, Y., & Rao, Y. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00220e · Cited by 313
Oncogenic protein interfaces: small molecules, big challenges
Nero, T. L., Morton, C. J., Holien, J. K., Wielens, J., & Parker, M. W. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3690 · Cited by 312
Li, Y., Yang, J., Aguilar, A., McEachern, D., Przybranowski, S., Liu, L., Yang, C.-Y., Wang, M., Han, X., & Wang, S. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00909 · Cited by 312
Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma
Qian, Y., Gong, Y., Fan, Z., Luo, G., Huang, Q., Deng, S., Cheng, H., Jin, K., Ni, Q., Yu, X., et al. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00958-3 · Cited by 312
Therapeutics targeting the innate immune system
Ulevitch, R. J. (2004) · Nature reviews. Immunology · doi:10.1038/nri1396 · Cited by 308
MDM2 is a Central Node in the p53 Pathway: 12 Years and Counting
Bond, G. L., Hu, W., & Levine, A. J. (2005) · Current Cancer Drug Targets · doi:10.2174/1568009053332627 · Cited by 310
A surface on the androgen receptor that allosterically regulates coactivator binding
Estébanez-Perpiñá, E., Arnold, L. A., Nguyen, P., Rodrigues, E. D., Mar, E., Bateman, R., Pallai, P., Shokat, K. M., Baxter, J. D., Guy, R. K., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0708036104 · Cited by 307
Mechanisms of protein-folding diseases at a glance
Valastyan, J. S., & Lindquist, S. L. (2014) · Disease Models & Mechanisms · doi:10.1242/dmm.013474 · Cited by 318
Lefort, K., Mandinova, A., Ostano, P., Kolev, V. N., Calpini, V., Kolfschoten, I., Devgan, V., Lieb, J., Raffoul, W., Hohl, D., et al. (2007) · Genes & Development · doi:10.1101/gad.1484707 · Cited by 313
Loughery, J., Cox, M. L., Smith, L. M., & Meek, D. W. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku501 · Cited by 326
p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis
Wang, X., Simpson, E. R., & Brown, K. A. (2015) · Cancer Research · doi:10.1158/0008-5472.can-15-0563 · Cited by 309
Exploiting replicative stress to treat cancer
Dobbelstein, M., & Sørensen, C. S. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4553 · Cited by 310
Targeting XIAP for the treatment of malignancy
Schimmer, A. D., Dalili, S., Batey, R. A., & Riedl, S. J. (2005) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401826 · Cited by 303
Structural basis for Cul3 protein assembly with the BTB-Kelch family of E3 ubiquitin ligases
Canning, P., Cooper, C. D. O., Krojer, T., Murray, J. W., Pike, A. C. W., Chaikuad, A., Keates, T., Thangaratnarajah, C., Hojzan, V., Marsden, B. D., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.437996 · Cited by 284
“Promisingly, small molecules have been identified previously that target the corepressor binding groove of the BCL6 BTB domain (61) as well as the substrate binding grooves of E3 ligases, including MDM2 (62), VHL (63), and Skp2 (64).”
Chen, J., Sawyer, N., & Regan, L. (2013) · Protein Science · doi:10.1002/pro.2230 · Cited by 305
The human long non-coding RNA-RoR is a p53 repressor in response to DNA damage
Zhang, A., Zhou, N., Huang, J., Liu, Q., Fukuda, K., Ma, D., Lü, Z., Bai, C., Watabe, K., & Mo, Y. (2012) · Cell Research · doi:10.1038/cr.2012.164 · Cited by 308
Pan, R., Ruvolo, V., Mu, H., Leverson, J. D., Nichols, G., Reed, J. C., Konopleva, M., & Andreeff, M. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.11.003 · Cited by 300
Targeting the MDM2–p53 Protein–Protein Interaction for New Cancer Therapy: Progress and Challenges
Wang, S., Zhao, Y., Aguilar, A., Bernard, D., & Yang, C.-Y. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026245 · Cited by 300
The Roles of MDM2 and MDMX in Cancer
Karni-Schmidt, O., Lokshin, M., & Prives, C. L. (2016) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-012414-040349 · Cited by 302
Unstructural biology coming of age
Tompa, P. (2011) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2011.03.012 · Cited by 292
Sur, S., Pagliarini, R. A., Bunz, F., Rago, C., Diaz, L. A., Kinzler, K. W., Vogelstein, B., & Papadopoulos, N. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0813333106 · Cited by 293
Cell-to-cell variation in p53 dynamics leads to fractional killing.
Paek, A. L., Liu, J. C., Loewer, A., Forrester, W. C., & Lahav, G. (2016) · Cell · doi:10.1016/j.cell.2016.03.025 · Cited by 292
Peptide-mediated interactions in biological systems: new discoveries and applications
Petsalaki, E., & Russell, R. B. (2008) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2008.06.004 · Cited by 291
The Influence of Cell Cycle Regulation on Chemotherapy
Sun, Y., Liu, Y., Ma, X., & Hu, H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22136923 · Cited by 320
Zhao, Y., Yu, S., Sun, W., Liu, L., Lü, J., McEachern, D., Shargary, S., Bernard, D., Li, X., Zhao, T., et al. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm4005708 · Cited by 296
Hepatocellular Carcinoma: Molecular Pathways and New Therapeutic Targets
Roberts, L. R., & Gores, G. J. (2005) · Seminars in Liver Disease · doi:10.1055/s-2005-871200 · Cited by 293
p53 Family and Cellular Stress Responses in Cancer
Pflaum, J., Schlosser, S., & ller, M. M. ⁄. (2014) · Frontiers in Oncology · doi:10.3389/fonc.2014.00285 · Cited by 309
Sun, D., Li, Z., Rew, Y., Gribble, M., Bartberger, M. D., Beck, H. P., Canon, J., Chen, A., Chen, X., Chow, D., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm401753e · Cited by 290
Tovar, C., Graves, B., Packman, K., Filipovic, Z., Xia, B. H. M., Tardell, C., Garrido, R., Lee, E., Kolinsky, K., To, K.-H., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-2807 · Cited by 283
Self-citationSmall‐Molecule Inhibitors of the Interaction between the E3 Ligase VHL and HIF1α
Buckley, D. L., Gustafson, J. L., Van Molle, I., Roth, A. G., Tae, H. S., Gareiss, P. C., Jorgensen, W. L., Ciulli, A., & Crews, C. M. (2012) · Angewandte Chemie International Edition · doi:10.1002/anie.201206231 · Cited by 302
Predicting protein druggability
Hajduk, P. J., Huth, J. R., & Tse, C. (2005) · Drug Discovery Today · doi:10.1016/s1359-6446(05)03624-x · Cited by 293
Hydrocarbon Stapled Peptides as Modulators of Biological Function
Cromm, P. M., Spiegel, J., & Grossmann, T. N. (2015) · ACS Chemical Biology · doi:10.1021/cb501020r · Cited by 294
Regulation of the p53 response and its relationship to cancer
Meek, D. W. (2015) · Biochemical Journal · doi:10.1042/bj20150517 · Cited by 311
Linke, K., Mace, P. D., Smith, C. A., Vaux, D. L., Silke, J., & Day, C. L. (2008) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4402309 · Cited by 288
Pathological Unfoldomics of Uncontrolled Chaos: Intrinsically Disordered Proteins and Human Diseases
Uversky, V. N., Davé, V., Iakoucheva, L. M., Malaney, P., Metallo, S. J., Pathak, R. R., & Joerger, A. C. (2014) · Chemical Reviews · doi:10.1021/cr400713r · Cited by 288
Smith, M. C. P., & Gestwicki, J. E. (2012) · Expert Reviews in Molecular Medicine · doi:10.1017/erm.2012.10 · Cited by 297
A Stapled p53 Helix Overcomes HDMX-Mediated Suppression of p53
Bernal, F., Wade, M. R., Godes, M., Davis, T. N., Whitehead, D. G., Kung, A. L., Wahl, G. M., & Walensky, L. D. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.10.024 · Cited by 288
The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2
Stevenson, L. F., Sparks, A., Allende‐Vega, N., Xirodimas, D. P., Lane, D. P., & Saville, M. K. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601567 · Cited by 280
A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidizationPreprint
Aylon, Y., Michael, D., Shmueli, A., Yabuta, N., Nojima, H., & Oren, M. (2006) · Genes & Development · doi:10.1101/gad.1447006 · Cited by 287
Apoptosis-based therapies and drug targets
Fischer, U., & Schulze‐Osthoff, K. (2005) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401556 · Cited by 283
Modulators of 14-3-3 Protein–Protein Interactions
Stevers, L. M., Sijbesma, E., Botta, M., MacKintosh, C., Obšil, T., Landrieu, I., Cau, Y., Wilson, A. J., Karawajczyk, A., Eickhoff, J., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00574 · Cited by 295
Mouse and human urothelial cancer organoids: A tool for bladder cancer research
Mullenders, J., de Jongh, E., Brousali, A., Roosen, M. M., Blom, J. P. A., Begthel, H., Korving, J., Jonges, T. G. N., Kranenburg, O., Meijer, R. P., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1803595116 · Cited by 287
The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes
Belgardt, B., Ahmed, K., Spranger, M., Latreille, M., Denzler, R., Kondratiuk, N., von Meyenn, F., Villena, F. N., Herrmanns, K., Bosco, D., et al. (2015) · Nature Medicine · doi:10.1038/nm.3862 · Cited by 283
The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway.
Korotchkina, L. G., Leontieva, O. V., Bukreeva, E. I., Demidenko, Z. N., Gudkov, A. V., & Blagosklonny, M. V. (2010) · Aging · doi:10.18632/aging.100160 · Cited by 278
Molecular Principles of the Interactions of Disordered Proteins
Mészáros, B., Tompa, P., Simon, I., & Dosztányi, Z. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.07.004 · Cited by 277
Abuetabh, Y., Wu, H. H., Chai, C., Yousef, H. A., Persad, S., Sergi, C. M., & Leng, R. P. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00863-4 · Cited by 280
Dou, Q. P., & Zonder, J. A. (2014) · Current Cancer Drug Targets · doi:10.2174/1568009614666140804154511 · Cited by 282
Targeting Transcription Factors in Cancer
Bhagwat, A. S., & Vakoc, C. R. (2015) · Trends in Cancer · doi:10.1016/j.trecan.2015.07.001 · Cited by 276
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 282
MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodelingPreprint
Venkatesh, D., O'Brien, N. A., Zandkarimi, F., Tong, D. R., Stokes, M. E., Dunn, D., Kengmana, E. S., Aron, A. T., Klein, A. M., Csuka, J. M., et al. (2020) · Genes & Development · doi:10.1101/gad.334219.119 · Cited by 274
Paradoxical suppression of cellular senescence by p53
Demidenko, Z. N., Korotchkina, L. G., Gudkov, A. V., & Blagosklonny, M. V. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1002298107 · Cited by 273
New targets and approaches in osteosarcoma
Gill, J. B., Ahluwalia, M., Geller, D., & Gorlick, R. G. (2012) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2012.09.003 · Cited by 274
Discovery of specific inhibitors of human USP7/HAUSP deubiquitinating enzyme.
Reverdy, C., Conrath, S., Lopez, R., Planquette, C., Atmanene, C., Collura, V., Harpon, J., Battaglia, V., Vivat, V., Sippl, W., et al. (2012) · Chemistry & Biology · doi:10.1016/j.chembiol.2012.02.007 · Cited by 270
Bassermann, F. C., Eichner, R., & Pagano, M. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.02.028 · Cited by 278
Gurova, K. V., Hill, J. E., Guo, C., Prokvolit, A., Burdelya, L. G., Samoylova, E. M., Khodyakova, A. V., Ganapathi, R. N., Ganapathi, M. K., Tararova, N. D., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508888102 · Cited by 266
Xiao, Y., Chen, J., Zhou, H., Zeng, X., Ruan, Z., Pu, Z., Jiang, X., Matsui, A., Zhu, L., Amoozgar, Z., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28279-8 · Cited by 269
Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs
Alabi, S. B., & Crews, C. M. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100647 · Cited by 279
Rayburn, E., Zhang, R., He, J., & Wang, H. (2005) · Current Cancer Drug Targets · doi:10.2174/1568009053332636 · Cited by 265
Transient protein-protein interactions
Acuner, S. E., Engin, H. B., Gürsoy, A., & Keskin, Ö. (2011) · Protein Engineering Design and Selection · doi:10.1093/protein/gzr025 · Cited by 275
Inhibition of protein–protein interactions using designed molecules
Wilson, A. J. (2009) · Chemical Society Reviews · doi:10.1039/b807197g · Cited by 262
Jiang, Z., Lu, M., Xu, L., Yang, T., Xi, M., Xu, X., Guo, X., Zhang, X., You, Q., & Sun, H.-P. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm5000529 · Cited by 263
Chen, D., Zhang, Z., Li, M., Wang, W., Li, Y., Rayburn, E. R., Hill, D. L., Wang, H., & Zhang, R. (2007) · Oncogene · doi:10.1038/sj.onc.1210327 · Cited by 265
The ubiquitin–proteasome pathway in Parkinson's disease and other neurodegenerative diseases
Ross, C. A., & Pickart, C. M. (2004) · Trends in Cell Biology · doi:10.1016/j.tcb.2004.10.006 · Cited by 261
Griveau, A., Seano, G., Shelton, S. J., Kupp, R., Jahangiri, A., Obernier, K., Krishnan, S., Lindberg, O. R., Yuen, T. J., Tien, A., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.03.020 · Cited by 264
Tisato, V., Voltan, R., Gonelli, A., Secchiero, P., & Zauli, G. (2017) · Journal of Hematology & Oncology · doi:10.1186/s13045-017-0500-5 · Cited by 259
Vousden, K. H., & Prives, C. L. (2005) · Cell · doi:10.1016/j.cell.2004.12.027 · Cited by 259
Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo
Ringshausen, I., O'Shea, C. C., Finch, A. J., Swigart, L. B., & Evan, G. I. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.10.010 · Cited by 256
New Approaches and Therapeutics Targeting Apoptosis in Disease
Fischer, U., & Schulze‐Osthoff, K. (2005) · Pharmacological Reviews · doi:10.1124/pr.57.2.6 · Cited by 259
Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure
Pagliarini, R. A., Shao, W., & Sellers, W. R. (2015) · EMBO Reports · doi:10.15252/embr.201439949 · Cited by 264
Smoking, p53 Mutation, and Lung Cancer
Gibbons, D. L., Byers, L. A., & Kurie, J. M. (2014) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-13-0539 · Cited by 255
Terphenyl‐Based Helical Mimetics That Disrupt the p53/HDM2 Interaction
Yin, H. H., Lee, G., Park, H. S., Payne, G. A., Rodriguez, J. M., Sebti, S. M., & Hamilton, A. D. (2005) · Angewandte Chemie International Edition · doi:10.1002/anie.200462316 · Cited by 260
CDK8 Is a Stimulus-Specific Positive Coregulator of p53 Target Genes
Donner, A. J., Szostek, S. A., Hoover, J. M., & Espinosa, J. M. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.05.026 · Cited by 253
Assemblages: Functional units formed by cellular phase separation
Toretsky, J. A., & Wright, P. E. (2014) · The Journal of Cell Biology · doi:10.1083/jcb.201404124 · Cited by 251
Intrinsically Disordered Proteins: An Overview
Trivedi, R., & Nagarajaram, H. A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232214050 · Cited by 277
Targeting p53 for Novel Anticancer Therapy
Wang, Z., & Sun, Y. (2010) · Translational Oncology · doi:10.1593/tlo.09250 · Cited by 256
Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia
Carvajal, L. A., Neriah, D. B., Senecal, A., Benard, L., Thiruthuvanathan, V., Yatsenko, T., Narayanagari, S.-R., Wheat, J. C., Todorova, T. I., Mitchell, K., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aao3003 · Cited by 249
Rational drug design via intrinsically disordered protein
Cheng, Y., LeGall, T., Oldfield, C. J., Mueller, J. P., Van, Y.-Y. J., Romero, P. R., Cortese, M. S., Uversky, V. N., & Dunker, A. K. (2006) · Trends in biotechnology · doi:10.1016/j.tibtech.2006.07.005 · Cited by 248
The nucleolus: an emerging target for cancer therapy
Hein, N., Hannan, K. M., George, A. J., Sanij, E., & Hannan, R. D. (2013) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2013.07.005 · Cited by 259
Metadata
- Authors
- Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., Fotouhi, N., & Liu, E. A.
- Affiliations
- Department of Discovery Oncology, Roche Research Center, Hoffmann–La Roche, Inc., Nutley, NJ 07110, USA.
- Corresponding author
- Vassilev, Lyubomir T.
- Venue
- Science
- Published
- 2004-02-06
- Volume
- 303
- Issue
- 5659
- Pages
- 844-848
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2097933346
- Cited by
- 4,661
- References
- 21
- Citations by year
- 2026: 119 · 2025: 166 · 2024: 169 · 2023: 203 · 2022: 204 · 2021: 199 · 2020: 226 · 2019: 212 · 2018: 216 · 2017: 209 · 2016: 258 · 2015: 248 · 2014: 296 · 2013: 273 · 2012: 265
- FWCI
- 83.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- MDM2, p53, small molecule antagonists, p53 stabilization, p53-MDM2 interaction, cancer therapy, cell cycle arrest, apoptosis, tumor xenografts, crystal structure
- MeSH terms
- Animals, Binding Sites, Cell Cycle, Cell Division, Cell Line, Cell Survival, Crystallization, Dose-Response Relationship, Drug, Humans, Imidazoles, Mice, Nude, Models, Molecular, Molecular Weight, Neoplasm Transplantation, Neoplasms, Experimental, Nuclear Proteins, Phosphorylation, Piperazines, Protein Conformation, Proto-Oncogene Proteins, Stereoisomerism, Transplantation, Heterologous, Gene Expression, Genes, p53, Tumor Suppressor Protein p53, Cyclins, Apoptosis, Crystallography, X-Ray, NIH 3T3 Cells, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21, Mice, Proto-Oncogene Proteins c-mdm2, Hydrophobic and Hydrophilic Interactions
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
