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.
Integrity signals
Registry
Cites
Statistics
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?
WB138 increases levels of both p53 and MDM2, consistent with previous reports on MDM2 inhibitors.
“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]
Nutlin-3a had the strongest activity, and its binding activity with MDM2 reached 90 nM.
“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]
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.
“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]
Inhibition of MDM2 binding to p53 or p73α appears more effective at promoting p53- and p73α-mediated apoptosis in cancer cells than in normal cells.
“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]
Nutlin-3a binds the N-terminal hydrophobic pocket of Mdm2 and blocks protein-protein interactions between Mdm2 and p53.
“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]
Nutlin treatment raises Mdm2 protein levels in cells regardless of whether p53 is present.
“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]
Nutlin blocks the interaction between Mdm2 and p53 and can activate p53 to cause apoptosis in cancer cells that retain wild-type p53.
“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 preclinical in vivo models, Mdm2 inhibition was tolerated by nonmalignant tissues without overt toxicity.
“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 mice, blocking the Mdm2-p53 interaction with small molecules causes tumors to shrink in a p53-dependent manner.
“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]
Small-molecule PPI antagonists that disrupt the p53-MDM2 interaction have been identified, including nutlin 3a and MI-219.
“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]
Nutlins are small molecules that bind MDM2 at the p53 interaction interface.
“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]
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 · see citing works
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 · see citing works
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 · see citing works
Vogelstein, B., Lane, D., & Levine, A. J. (2000) · Nature · doi:10.1038/35042675 · Cited by 6,607 · see citing works
Requirement for p53 and p21 to Sustain G <sub>2</sub> 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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 1,447 · see citing works
The MDM2 gene amplification database
Momand, J. (1998) · Nucleic Acids Research · doi:10.1093/nar/26.15.3453 · Cited by 982 · see citing works
Inhibiting the p53–MDM2 interaction: an important target for cancer therapy
Chène, P. (2003) · Nature Reviews Cancer · doi:10.1038/nrc991 · Cited by 765 · see citing works
The p53–Mdm2 module and the ubiquitin system
Michael, D., & Oren, M. (2002) · Seminars in Cancer Biology · doi:10.1016/s1044-579x(02)00099-8 · Cited by 759 · see citing works
Ashcroft, M. A., & Vousden, K. H. (1999) · Oncogene · doi:10.1038/sj.onc.1203012 · Cited by 407 · see citing works
Design of a synthetic Mdm2-binding mini protein that activates the p53 response in vivo
Böttger, A., Böttger, V., Sparks, A., Liu, W.-L., Howard, S. F., & Lane, D. P. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00374-5 · Cited by 363 · see citing works
Serum insulin-like growth factor-I and breast cancer
Toniolo, P. G., Bruning, P. F., Akhmedkhanov, A., Bonfrèr, J. M. G., Koenig, K. L., Lukanova, A., Shore, R. E., & Zeleniuch‐Jacquotte, A. (2000) · International Journal of Cancer · doi:10.1002/1097-0215(20001201)88:5 · Cited by 341 · see citing works
Retinoids: present role and future potential
Evans, T. R. J., & Kaye, S. B. (1999) · British Journal of Cancer · doi:10.1038/sj.bjc.6690312 · Cited by 218 · see citing works
Picksley, S. M., & Lane, D. P. (1993) · BioEssays · doi:10.1002/bies.950151008 · Cited by 207 · see citing works
Jimenez, G. S., Khan, S. H., Stommel, J. M., & Wahl, G. M. (1999) · Oncogene · doi:10.1038/sj.onc.1203013 · Cited by 176 · see citing works
Synergistic activation of p53 by inhibition of MDM2 expression and DNA damage
Chen, L., Agrawal, S., Zhou, W., Zhang, R., & Chen, J. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.1.195 · Cited by 159 · see citing works
Chêne, P., Fuchs, J. P., Bohn, J. A., Garcı́a-Echeverrı́a, C., Furet, P., & Fabbro, D. (2000) · Journal of Molecular Biology · doi:10.1006/jmbi.2000.3738 · Cited by 139 · see citing works
p53 mediated death of cells overexpressing MDM2 by an inhibitor of MDM2 interaction with p53
Wasylyk, C., Salvi, R., Argentini, M., Dureuil, C., Delumeau, I., Abecassis, J., Debüssche, L., & Wasylyk, B. (1999) · Oncogene · doi:10.1038/sj.onc.1202528 · Cited by 112 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Blinded by the Light: The Growing Complexity of p53
Vousden, K. H., & Prives, C. (2009) · Cell · doi:10.1016/j.cell.2009.04.037 · Cited by 3,163 · see citing works
Systematic identification of genomic markers of drug sensitivity in cancer cells
Garnett, M. J., Edelman, E. J., Heidorn, S. J., Greenman, C. D., Dastur, A., Lau, K. W., Greninger, P., Thompson, I. R., Luo, X., Soares, J., et al. (2012) · Nature · doi:10.1038/nature11005 · Cited by 2,456 · see citing works
The re-emergence of natural products for drug discovery in the genomics era
Harvey, A. L., Edrada‐Ebel, R., & Quinn, R. J. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4510 · Cited by 2,601 · see citing works
Chemistry and Biology Of Multicomponent Reactions
Dömling, A. S. S., Wang, W., & Wang, K. (2012) · Chemical Reviews · doi:10.1021/cr100233r · Cited by 2,572 · see citing works
Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
Xue, W., Zender, L., Miething, C., Dickins, R. A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., & Lowe, S. W. (2007) · Nature · doi:10.1038/nature05529 · Cited by 2,473 · see citing works
Galliford, C. V., & Scheidt, K. A. (2007) · Angewandte Chemie International Edition · doi:10.1002/anie.200701342 · Cited by 2,431 · see citing works
Prospective Derivation of a Living Organoid Biobank of Colorectal Cancer Patients
van de Wetering, M., Francies, H. E., Francis, J. M., Bounova, G., Iorio, F., Pronk, A., van Houdt, W., van Gorp, J., Taylor-Weiner, A., Kester, L., et al. (2015) · Cell · doi:10.1016/j.cell.2015.03.053 · Cited by 2,408 · see citing works
Vousden, K. H., & Lane, D. P. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2147 · Cited by 2,275 · see citing works
TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis
Bensaad, K., Tsuruta, A., Selak, M. A., Vidal, M. N. C., Nakano, K., Bartrons, R., Gottlieb, E., & Vousden, K. H. (2006) · Cell · doi:10.1016/j.cell.2006.05.036 · Cited by 2,019 · see citing works
The first 30 years of p53: growing ever more complex.
Levine, A. J., & Oren, M. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2723 · Cited by 1,967 · see citing works
Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis
Chen, Z., Trotman, L. C., Shaffer, D., Lin, H.-K., Dotan, Z. A., Niki, M., Koutcher, J. A., Scher, H. I., Ludwig, T., Gerald, W., et al. (2005) · Nature · doi:10.1038/nature03918 · Cited by 1,993 · see citing works
Kastenhuber, E. R., & Lowe, S. W. (2017) · Cell · doi:10.1016/j.cell.2017.08.028 · Cited by 1,906 · see citing works
Reaching for high-hanging fruit in drug discovery at protein–protein interfaces
Wells, J. A., & McClendon, C. L. (2007) · Nature · doi:10.1038/nature06526 · Cited by 1,963 · see citing works
Restoration of p53 function leads to tumour regression in vivo
Ventura, A., Kirsch, D. G., McLaughlin, M. E., Tuveson, D. A., Grimm, J., Lintault, L., Newman, J., Reczek, E. E., Weissleder, R., & Jacks, T. (2007) · Nature · doi:10.1038/nature05541 · Cited by 1,820 · see citing works
Small-molecule inhibitors of protein–protein interactions: progressing towards the dream
Arkin, M. R., & Wells, J. A. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1343 · Cited by 1,705 · see citing works
Pistritto, G., Trisciuoglio, D., Ceci, C., Garufi, A., & D’Orazi, G. (2016) · Aging · doi:10.18632/aging.100934 · Cited by 1,670 · see citing works
Kruse, J.-P., & Gu, W. (2009) · Cell · doi:10.1016/j.cell.2009.04.050 · Cited by 1,610 · see citing works
Induced protein degradation: an emerging drug discovery paradigm
Lai, A. C., & Crews, C. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.211 · Cited by 1,486 · see citing works
Paul Ehrlich's magic bullet concept: 100 years of progress
Strebhardt, K., & Ullrich, A. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2394 · Cited by 1,461 · see citing works
How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression
Aubrey, B. J., Kelly, G. L., Janic, A., Herold, M. J., & Strasser, A. (2018) · Cell Death & Differentiation · doi:10.1038/cdd.2017.169 · Cited by 1,395 · see citing works
Ubiquitin ligases: cell-cycle control and cancer
Nakayama, K. I., & Nakayama, K. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1881 · Cited by 1,441 · see citing works
Intrinsically Disordered Proteins in Human Diseases: Introducing the D 2 Concept
Uversky, V. N., Oldfield, C. J., & Dunker, A. K. (2008) · Annual Review of Biophysics · doi:10.1146/annurev.biophys.37.032807.125924 · Cited by 1,406 · see citing works
Ubiquitin: structures, functions, mechanisms
Pickart, C. M., & Eddins, M. J. (2004) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2004.09.019 · Cited by 1,406 · see citing works
Cyclin D as a therapeutic target in cancer
Musgrove, E. A., Caldon, C. E., Barraclough, J., Stone, A., & Sutherland, R. L. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3090 · Cited by 1,370 · see citing works
p53 Target Genes Sestrin1 and Sestrin2 Connect Genotoxic Stress and mTOR Signaling
Budanov, A. V., & Karin, M. (2008) · Cell · doi:10.1016/j.cell.2008.06.028 · Cited by 1,326 · see citing works
Cellular Senescence: Aging, Cancer, and Injury
Calcinotto, A., Kohli, J., Zagato, E., Pellegrini, L., Demaria, M., & Alimonti, A. (2019) · Physiological Reviews · doi:10.1152/physrev.00020.2018 · Cited by 1,270 · see citing works
MDM2, MDMX and p53 in oncogenesis and cancer therapy
Wade, M., Li, Y.-C., & Wahl, G. M. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3430 · Cited by 1,279 · see citing works
Regulating the p53 pathway: in vitro hypotheses, in vivo veritas
Toledo, F., & Wahl, G. M. (2006) · Nature reviews. Cancer · doi:10.1038/nrc2012 · Cited by 1,286 · see citing works
Understanding protein non-folding
Uversky, V. N., & Dunker, A. K. (2010) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2010.01.017 · Cited by 1,188 · see citing works
Modeling colorectal cancer using CRISPR-Cas9–mediated engineering of human intestinal organoids
Matano, M., Date, S., Shimokawa, M., Takano, A., Fujii, M., Ohta, Y., Watanabe, T., Kanai, T., & Sato, T. (2015) · Nature Medicine · doi:10.1038/nm.3802 · Cited by 1,135 · see citing works
Regulation of autophagy by cytoplasmic p53
Tasdemir, E., Maiuri, M. C., Galluzzi, L., Vitale, I., Djavaheri-Mergny, M., D'Amelio, M., Criollo, A., Morselli, E., Zhu, C., Harper, F., et al. (2008) · Nature Cell Biology · doi:10.1038/ncb1730 · Cited by 1,132 · see citing works
Linking the p53 tumour suppressor pathway to somatic cell reprogramming
Kawamura, T., Suzuki, J., Wang, Y. V., Menendez, S., Morera, L. B., Raya, A., Wahl, G. M., & Belmonte, J. C. I. (2009) · Nature · doi:10.1038/nature08311 · Cited by 1,115 · see citing works
Small molecules, big targets: drug discovery faces the protein–protein interaction challenge
Scott, D. E., Bayly, A. R., Abell, C., & Skidmore, J. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.29 · Cited by 1,137 · see citing works
The SCF ubiquitin ligase: insights into a molecular machine
Cardozo, T., & Pagano, M. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1471 · Cited by 1,114 · see citing works
Promoting apoptosis as a strategy for cancer drug discovery
Fesik, S. W. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1736 · Cited by 1,095 · see citing works
Small-Molecule Inhibitors of Protein-Protein Interactions: Progressing toward the Reality
Arkin, M. R., Tang, Y., & Wells, J. A. (2014) · Chemistry & Biology · doi:10.1016/j.chembiol.2014.09.001 · Cited by 1,065 · see citing works
Sequential cancer mutations in cultured human intestinal stem cells
Drost, J., van Jaarsveld, R. H., Ponsioen, B., Zimberlin, C., van Boxtel, R., Buijs, A., Sachs, N., Overmeer, R. M., Offerhaus, G. J., Begthel, H., et al. (2015) · Nature · doi:10.1038/nature14415 · Cited by 1,067 · see citing works
Long‐term expanding human airway organoids for disease modeling
Sachs, N., Papaspyropoulos, A., Zomer‐van Ommen, D. D., Heo, I., Böttinger, L., Klay, D., Weeber, F., Huelsz‐Prince, G., Iakobachvili, N., Amatngalim, G. D., et al. (2019) · The EMBO Journal · doi:10.15252/embj.2018100300 · Cited by 1,082 · see citing works
The development of the concept of ferroptosis
Hirschhorn, T., & Stockwell, B. R. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.09.043 · Cited by 1,052 · see citing works
Tenets of PTEN Tumor Suppression
Salmena, L., Carracedo, A., & Pandolfi, P. P. (2008) · Cell · doi:10.1016/j.cell.2008.04.013 · Cited by 1,027 · see citing works
iRegulon: From a Gene List to a Gene Regulatory Network Using Large Motif and Track Collections
Janky, R., Verfaillie, A., Imrichová, H., Van de Sande, B., Standaert, L., Christiaens, V., Hulselmans, G., Herten, K., Naval Sanchez, M., Potier, D., et al. (2014) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003731 · Cited by 900 · see citing works
“Wefirstdetermined a p53-dependent gene signature in the MCF-7 human breast cancer cell line by RNA-seq upon stabilization of p53 by the non-genotoxic small molecule Nutlin-3a [57].”
BackgroundTargeting transcription factors in cancer — from undruggable to reality
Bushweller, J. H. (2019) · Nature Reviews Cancer · doi:10.1038/s41568-019-0196-7 · Cited by 919 · see citing works
p53 inhibits CRISPR–Cas9 engineering in human pluripotent stem cells
Ihry, R. J., Worringer, K. A., Salick, M. R., Frias, E., Ho, D., Theriault, K., Kommineni, S., Chen, J., Sondey, M., Ye, C., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0050-6 · Cited by 978 · see citing works
Lu, H., Zhou, Q., He, J., Jiang, Z., Peng, C., Tong, R., & Shi, J. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00315-3 · Cited by 891 · see citing works
p53 ubiquitination: Mdm2 and beyond
Brooks, C. L., & Gu, W. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.020 · Cited by 924 · see citing works
Awakening guardian angels: drugging the p53 pathway
Brown, C. J., Lain, S., Verma, C. S., Fersht, A. R., & Lane, D. P. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2763 · Cited by 881 · see citing works
Exploiting senescence for the treatment of cancer
Wang, L., Lankhorst, L., & Bernards, R. (2022) · Nature Reviews Cancer · doi:10.1038/s41568-022-00450-9 · Cited by 867 · see citing works
Understanding Apoptosis and Apoptotic Pathways Targeted Cancer Therapeutics
Jan, R., & Chaudhry, G.-E.-S. (2019) · Advanced Pharmaceutical Bulletin · doi:10.15171/apb.2019.024 · Cited by 919 · see citing works
Structure and dynamics of molecular networks: A novel paradigm of drug discovery
Csermely, P., Korcsmáros, T., Kiss, H., London, G., & Nussinov, R. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.01.016 · Cited by 889 · see citing works
Spirooxindoles: Promising scaffolds for anticancer agents
Yu, B., Yu, D., & Liu, H. (2014) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2014.06.056 · Cited by 870 · see citing works
An organoid platform for ovarian cancer captures intra- and interpatient heterogeneity
Kopper, O., de Witte, C. J., Lõhmussaar, K., Valle-Inclan, J. E., Hami, N., Kester, L., Balgobind, A. V., Korving, J., Proost, N., Begthel, H., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0422-6 · Cited by 834 · see citing works
Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies
Lipson, D., Capelletti, M., Yelensky, R., Otto, G., Parker, A., Jarosz, M., Curran, J. A., Balasubramanian, S., Bloom, T., Brennan, K. W., et al. (2012) · Nature Medicine · doi:10.1038/nm.2673 · Cited by 869 · see citing works
PROteolysis TArgeting Chimeras (PROTACs) — Past, present and future
Pettersson, M., & Crews, C. M. (2019) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2019.01.002 · Cited by 818 · see citing works
p53 Dynamics Control Cell Fate
Purvis, J. E., Karhohs, K. W., Mock, C., Batchelor, E., Loewer, A., & Lahav, G. (2012) · Science · doi:10.1126/science.1218351 · Cited by 770 · see citing works
Targeting the Cell Cycle: A New Approach to Cancer Therapy
Schwartz, G. K., & Shah, M. A. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.01.5594 · Cited by 816 · see citing works
Hatakeyama, S. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3139 · Cited by 805 · see citing works
Selective small-molecule inhibitor reveals critical mitotic functions of human CDK1
Vassilev, L. T., Tovar, C., Chen, S., Knezevic, D., Zhao, X., Sun, H., Heimbrook, D. C., & Chen, L. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600447103 · Cited by 800 · see citing works
Self-citationIntrinsic Disorder in Transcription Factors
Liu, J., Perumal, N. B., Oldfield, C. J., Su, E. W., Uversky, V. N., & Dunker, A. K. (2006) · Biochemistry · doi:10.1021/bi0602718 · Cited by 792 · see citing works
Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses
Ou, Y., Wang, S.-J., Li, D., Chu, B., & Gu, W. J. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1607152113 · Cited by 775 · see citing works
The ubiquitin-proteasome system
Nandi, D., Tahiliani, P., Kumar, A., & Chandu, D. (2006) · Journal of Biosciences · doi:10.1007/bf02705243 · Cited by 767 · see citing works
Introducing Protein Intrinsic Disorder
Habchi, J., Tompa, P., Longhi, S., & Uversky, V. N. (2014) · Chemical Reviews · doi:10.1021/cr400514h · Cited by 744 · see citing works
Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting
Borrero, L. J. H., & El‐Deiry, W. S. (2021) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2021.188556 · Cited by 773 · see citing works
Small molecule RITA binds to p53, blocks p53–HDM-2 interaction and activates p53 function in tumors
Issaeva, N., Bozko, P. M., Enge, M., Protopopova, M., Verhoef, L. G. G. C., Masucci, M. G., Pramanik, A., & Selivanova, G. (2004) · Nature Medicine · doi:10.1038/nm1146 · Cited by 749 · see citing works
Tumor biomarkers for diagnosis, prognosis and targeted therapy
Zhou, Y., Tao, L., Qiu, J., Xu, J., Yang, X., Zhang, Y., Tian, X., Guan, X., Cen, X., & Zhao, Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01823-2 · Cited by 772 · see citing works
Role of p53 in Cell Death and Human Cancers
Ozaki, T., & Nakagawara, A. (2011) · Cancers · doi:10.3390/cancers3010994 · Cited by 743 · see citing works
IRF4 addiction in multiple myeloma
Shaffer, A. L., Emre, N. C. T., Lamy, L., Ngo, V. N., Wright, G., Xiao, W., Powell, J., Dave, S., Yu, X., Zhao, H., et al. (2008) · Nature · doi:10.1038/nature07064 · Cited by 730 · see citing works
Inhibition of α-helix-mediated protein–protein interactions using designed molecules
Azzarito, V., Long, K., Murphy, N. S., & Wilson, A. J. (2013) · Nature Chemistry · doi:10.1038/nchem.1568 · Cited by 727 · see citing works
Drugging p53 in cancer: one protein, many targets
Hassin, O., & Oren, M. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00571-8 · Cited by 736 · see citing works
Drugging the p53 pathway: understanding the route to clinical efficacy
Khoo, K. H., Verma, C. S., & Lane, D. P. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4236 · Cited by 723 · see citing works
Pelay‐Gimeno, M., Glas, A., Koch, O., & Grossmann, T. N. (2015) · Angewandte Chemie International Edition · doi:10.1002/anie.201412070 · Cited by 718 · see citing works
Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy
Tovar, C., Rosinski, J., Filipovic, Z., Higgins, B., Kolinsky, K., Hilton, H., Zhao, X., Vu, B. T., Qing, W., Packman, K., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507493103 · Cited by 708 · see citing works
Self-citationThe complexity of p53 stabilization and activation
Lavin, M. F., & Gueven, N. (2006) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401925 · Cited by 701 · see citing works
Ding, K., Lu, Y., Nikolovska-Coleska, Z., Wang, G., Qiu, S., Shangary, S., Gao, W., Qin, D., Stuckey, J., Krajewski, K., et al. (2006) · Journal of Medicinal Chemistry · doi:10.1021/jm051122a · Cited by 702 · see citing works
Apoptosis: a basic biological phenomenon with wide‐ranging implications in human disease
Fadeel, B., & Orrenius, S. (2005) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2005.01570.x · Cited by 699 · see citing works
Structure-based maximal affinity model predicts small-molecule druggability
Cheng, A. C., Coleman, R. G., Smyth, K. T., Cao, Q., Soulard, P., Caffrey, D. R., Salzberg, A. C., & Huang, E. S. (2007) · Nature Biotechnology · doi:10.1038/nbt1273 · Cited by 694 · see citing works
The Significance of Chirality in Drug Design and Development
Brooks, W. H., Guida, W. C., & Daniel, K. G. (2011) · Current Topics in Medicinal Chemistry · doi:10.2174/156802611795165098 · Cited by 697 · see citing works
The Tumor Suppressor p53 Regulates Polarity of Self-Renewing Divisions in Mammary Stem Cells
Cicalese, A., Bonizzi, G., Pasi, C. E., Faretta, M., Ronzoni, S., Giulini, B., Brisken, C., Minucci, S., Fiore, P. P. D., & Pelicci, P. G. (2009) · Cell · doi:10.1016/j.cell.2009.06.048 · Cited by 695 · see citing works
Structural Biology of the Tumor Suppressor p53
Joerger, A. C., & Fersht, A. R. (2008) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.77.060806.091238 · Cited by 699 · see citing works
Novel trends in high-throughput screening
Mayr, L. M., & Bojanic, D. (2009) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2009.08.004 · Cited by 690 · see citing works
The genetics of the p53 pathway, apoptosis and cancer therapy
Vázquez, A., Bond, E. E., Levine, A. J., & Bond, G. L. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2656 · Cited by 674 · see citing works
The role of ubiquitination in tumorigenesis and targeted drug discovery
Deng, L., Meng, T., Chen, L., Wei, W., & Wang, P. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0107-0 · Cited by 744 · see citing works
Chang, Y. S., Graves, B. J., Guerlavais, V., Tovar, C., Packman, K. E., To, K.-H., Olson, K. A., Kesavan, K. P., Gangurde, P., Mukherjee, A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1303002110 · Cited by 666 · see citing works
Self-citationAdvancing targeted protein degradation for cancer therapy
Dale, B., Cheng, M., Park, K., Kanıskan, H. Ü., Xiong, Y., & Jin, J. J. (2021) · Nature reviews. Cancer · doi:10.1038/s41568-021-00365-x · Cited by 671 · see citing works
The p53 Pathway: Origins, Inactivation in Cancer, and Emerging Therapeutic Approaches
Joerger, A. C., & Fersht, A. R. (2016) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060815-014710 · Cited by 658 · see citing works
Establishment of patient-derived cancer organoids for drug-screening applications
Driehuis, E., Kretzschmar, K., & Clevers, H. C. (2020) · Nature Protocols · doi:10.1038/s41596-020-0379-4 · Cited by 656 · see citing works
Small‐Molecule PROTACS: New Approaches to Protein Degradation
Toure, M., & Crews, C. M. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201507978 · Cited by 674 · see citing works
The P53 pathway: what questions remain to be explored?
Levine, A. J., Hu, W., & Feng, Z. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401910 · Cited by 654 · see citing works
Shangary, S., Qin, D., McEachern, D., Liu, M., Miller, R. S., Qiu, S., Nikolovska-Coleska, Z., Ding, K., Wang, G., Chen, J., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0708917105 · Cited by 660 · see citing works
Role of p53 in the Regulation of Cellular Senescence
Mijit, M., Caracciolo, V., Melillo, A., Amicarelli, F., & Giordano, A. (2020) · Biomolecules · doi:10.3390/biom10030420 · Cited by 639 · see citing works
Structure-based design of potent non-peptide MDM2 inhibitors
Ding, K., Lu, Y., Nikolovska-Coleska, Z., Qiu, S., Ding, Y., Gao, W., Stuckey, J., Krajewski, K., Roller, P. P., Tomita, Y., et al. (2005) · Journal of the American Chemical Society · doi:10.1021/ja051147z · Cited by 657 · see citing works
Erlanson, D. A., McDowell, R. S., & O'Brien, T. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm040031v · Cited by 645 · see citing works
PROTACs: great opportunities for academia and industry
Sun, X., Gao, H., Yang, Y., He, M., Wu, Y., Song, Y.-G., Tong, Y., & Rao, Y. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0101-6 · Cited by 651 · see citing works
Binh, M. B. N., Sastre‐Garau, X., Guillou, L., Pinieux, G. D. B. D., Terrier, P., Lagacé, R., Aurias, A., Hostein, I., & Coindre, J. (2005) · The American Journal of Surgical Pathology · doi:10.1097/01.pas.0000170343.09562.39 · Cited by 642 · see citing works
Intrinsically disordered proteins: a 10-year recap
Tompa, P. (2012) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2012.08.004 · Cited by 624 · see citing works
Shangary, S., & Wang, S. (2009) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.48.113006.094723 · Cited by 623 · see citing works
The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance
Bouwman, P., & Jonkers, J. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3342 · Cited by 615 · see citing works
Mutational processes shape the landscape of TP53 mutations in human cancer
Giacomelli, A. O., Yang, X., Lintner, R. E., McFarland, J. M., Duby, M., Kim, J., Howard, T. P., Takeda, D. Y., Ly, S. H., Kim, E., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0204-y · Cited by 556 · see citing works
Drug discovery in the ubiquitin–proteasome system
Nalepa, G., Rolfe, M., & Harper, J. W. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2056 · Cited by 619 · see citing works
What made sesquiterpene lactones reach cancer clinical trials?
Ghantous, A., Gali‐Muhtasib, H. U., Vuorela, H. J., Saliba, N. A., & Darwiche, N. (2010) · Drug Discovery Today · doi:10.1016/j.drudis.2010.06.002 · Cited by 618 · see citing works
Schneekloth, A. R., Pucheault, M., Tae, H. S., & Crews, C. M. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.07.114 · Cited by 635 · see citing works
- 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
