Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX
Open accessAbstract
The oncoproteins MDM2 and MDMX negatively regulate the activity and stability of the tumor suppressor protein p53—a cellular process initiated by MDM2 and/or MDMX binding to the N-terminal transactivation domain of p53. MDM2 and MDMX in many tumors confer p53 inactivation and tumor survival, and are important molecular targets for anticancer therapy. We screened a duodecimal peptide phage library against site-specifically biotinylated p53-binding domains of human MDM2 and MDMX chemically synthesized via native chemical ligation, and identified several peptide inhibitors of the p53-MDM2/MDMX interactions. The most potent inhibitor (TSFAEYWNLLSP), termed PMI, bound to MDM2 and MDMX at low nanomolar affinities—approximately 2 orders of magnitude stronger than the wild-type p53 peptide of the same length (ETFSDLWKLLPE). We solved the crystal structures of synthetic MDM2 and MDMX, both in complex with PMI, at 1.6 Å resolution. Comparative structural analysis identified an extensive, tightened intramolecular H-bonding network in bound PMI that contributed to its conformational stability, thus enhanced binding to the 2 oncogenic proteins. Importantly, the C-terminal residue Pro of PMI induced formation of a hydrophobic cleft in MDMX previously unseen in the structures of p53-bound MDM2 or MDMX. Our findings deciphered the structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX, shedding new light on structure-based rational design of different classes of p53 activators for potential therapeutic use.
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MDM2 amplification is frequently observed in several cancer types, especially tumors retaining wild-type p53.
“MDM2 amplification is frequently observed in several cancer types, especially in tumors that still retain wild-type p53.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [216]
Disrupting the MDM2-p53 interaction presents a potential approach for treating cancer by restoring the impaired function of p53.
“Therefore, disrupting the MDM2-p53 interaction, presents a potential approach for treating cancer by restoring the impaired function of p53.216,217”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [216]
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<i>Coot</i> : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571 · see citing works
Kabsch, W., & Sander, C. (1983) · Biopolymers · doi:10.1002/bip.360221211 · Cited by 15,320 · see citing works
Refinement of Macromolecular Structures by the Maximum-Likelihood Method
Murshudov, G. N., Vagin, A. A., & Dodson, E. J. (1997) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444996012255 · Cited by 14,671 · see citing works
Vogelstein, B., Lane, D., & Levine, A. J. (2000) · Nature · doi:10.1038/35042675 · Cited by 6,607 · see citing works
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004) · Science · doi:10.1126/science.1092472 · Cited by 4,661 · see citing works
Mdm2 promotes the rapid degradation of p53
Haupt, Y., Maya, R., Kazaz, A., & Oren, M. (1997) · Nature · doi:10.1038/387296a0 · Cited by 4,506 · see citing works
Synthesis of Proteins by Native Chemical Ligation
Dawson, P. E., Muir, T. W., Clark‐Lewis, I., & Kent, S. B. H. (1994) · Science · doi:10.1126/science.7973629 · Cited by 4,142 · see citing works
How to measure and predict the molar absorption coefficient of a protein
Pace, C., Vajdos, F., Fee, L. R., Grimsley, G., & Gray, T. (1995) · Protein Science · doi:10.1002/pro.5560041120 · Cited by 3,924 · see citing works
Regulation of p53 stability by Mdm2
Kubbutat, M. H. G., Jones, S. N., & Vousden, K. H. (1997) · Nature · doi:10.1038/387299a0 · Cited by 3,312 · see citing works
Live or let die: the cell's response to p53
Vousden, K. H., & Lü, X. (2002) · Nature reviews. Cancer · doi:10.1038/nrc864 · Cited by 3,177 · 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
Vousden, K. H., & Lane, D. P. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2147 · Cited by 2,275 · 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
Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53
Honda, R., Tanaka, H., & Yasuda, H. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)01480-4 · Cited by 1,951 · 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
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
Likelihood-enhanced fast rotation functions
Storoni, L. C., McCoy, A. J., & Read, R. J. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444903028956 · Cited by 1,177 · see citing works
Synthesis of Native Proteins by Chemical Ligation
Dawson, P. E., & Kent, S. B. H. (2000) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.69.1.923 · Cited by 1,084 · see citing works
Massova, I., & Kollman, P. A. (1999) · Journal of the American Chemical Society · doi:10.1021/ja990935j · Cited by 778 · 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
Self-citationLin, J., Chen, J., Elenbaas, B., & Levine, A. J. (1994) · Genes & Development · doi:10.1101/gad.8.10.1235 · Cited by 652 · see citing works
MDMX: a novel p53‐binding protein with some functional properties of MDM2.
Shvarts, A., Steegenga, W. T., Riteco, N., van Laar, T., Dekker, P., Bazuine, M., van Ham, R. C., van der Houven van Oordt, W., Hateboer, G., van der Eb, A. J., et al. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00919.x · Cited by 648 · see citing works
Modeling the Therapeutic Efficacy of p53 Restoration in Tumors
Martins, C. P., Brown-Swigart, L., & Evan, G. I. (2006) · Cell · doi:10.1016/j.cell.2006.12.007 · Cited by 600 · see citing works
Cell-penetrating and cell-targeting peptides in drug delivery
Vivès, É., Schmidt, J., & Pèlegrin, A. (2008) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2008.03.001 · Cited by 442 · see citing works
Discovery and Cocrystal Structure of Benzodiazepinedione HDM2 Antagonists That Activate p53 in Cells
Grasberger, B. L., Lu, T., Schubert, C., Parks, D. J., Carver, T. E., Koblish, H. K., Cummings, M. D., LaFrance, L. V., Milkiewicz, K. L., Calvo, R. R., et al. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm049137g · Cited by 433 · see citing works
Accelerated MDM2 auto‐degradation induced by DNA‐damage kinases is required for p53 activation
Stommel, J. M., & Wahl, G. M. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600145 · Cited by 386 · see citing works
Molecular Mechanism of the Interaction between MDM2 and p53
Schön, O., Friedler, A., Bycroft, M., Freund, S. M. V., & Fersht, A. R. (2002) · Journal of Molecular Biology · doi:10.1016/s0022-2836(02)00852-5 · Cited by 349 · see citing works
Tumor-suppressor p53: implications for tumor development and prognosis.
Kirsch, D. G., & Kastan, M. B. (1998) · Journal of Clinical Oncology · doi:10.1200/jco.1998.16.9.3158 · Cited by 301 · see citing works
Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells <i>in vivo</i>
Francoz, S., Froment, P., Bogaerts, S., De Clercq, S., Maetens, M., Doumont, G., Bellefroid, E., & Marine, J.-C. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508476103 · Cited by 260 · see citing works
Molecular characterization of the hdm2-p53 interaction 1 1Edited by J. Karn
Böttger, A., Böttger, V., Garcı́a-Echeverrı́a, C., Chêne, P., Hochkeppel, H. K., Sampson, W. R., Ang, K. H., Howard, S. F., Picksley, S. M., & Lane, D. P. (1997) · Journal of Molecular Biology · doi:10.1006/jmbi.1997.1078 · Cited by 251 · see citing works
MDM2 promotes ubiquitination and degradation of MDMX
Pan, Y., & Chen, J. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.15.5113-5121.2003 · Cited by 246 · see citing works
Picksley, S. M., Vojtĕsek, B., Sparks, A., & Lane, D. P. (1994) · PubMed · Cited by 238 · see citing works
Marine, J.-C. W., Dyer, M. A., & Jochemsen, A. G. (2007) · Journal of Cell Science · doi:10.1242/jcs.03362 · Cited by 228 · see citing works
Efficient p53 Activation and Apoptosis by Simultaneous Disruption of Binding to MDM2 and MDMX
Hu, B., Gilkes, D. M., & Chen, J. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1140 · Cited by 214 · see citing works
MdmX Protects p53 from Mdm2-Mediated Degradation
Jackson, M. W., & Berberich, S. J. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.3.1001-1007.2000 · Cited by 211 · cited 1× · see citing works
“Structurally related to MDM2, MDMX of 490-aa residues possesses domain structures arranged similarly to MDM2, except that MDMX lacks ubiquitin-ligase function (11, 12).”
BackgroundToledo, F., Krummel, K. A., Lee, C. J., Liu, C.-W., Rodewald, L.-W., Tang, M., & Wahl, G. M. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.03.014 · Cited by 199 · cited 1× · see citing works
“Growing evidence supports that in unstressed cells MDM2 primarily controls p53 stability through ubiquitylation to target the tumor suppressor protein for constitutive degradation by the proteasome (13, 14), whereas MDMX mainly functions as a significant p53 transcriptional antagonist independently of MDM2 (15, 16).”
BackgroundStructure of the human Mdmx protein bound to the p53 tumor suppressor transactivation domain
Popowicz, G. M., Czarna, A., & Holak, T. A. (2008) · Cell Cycle · doi:10.4161/cc.6365 · Cited by 195 · see citing works
Targeting protein–protein interactions: Lessons from p53/MDM2
Murray, J. K., & Gellman, S. H. (2007) · Biopolymers · doi:10.1002/bip.20741 · Cited by 186 · see citing works
Identification of novel mdm2 binding peptides by phage display.
Böttger, V., Böttger, A., Howard, S. F., Picksley, S. M., Chêne, P., Garcı́a-Echeverrı́a, C., Hochkeppel, H. K., & Lane, D. P. (1996) · PubMed · Cited by 182 · see citing works
DNA damage-induced MDMX degradation is mediated by MDM2
Kawai, H., Wiederschain, D., Kitao, H., Stuart, J., Tsai, K. K. C., & Yuan, Z.-M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m308295200 · Cited by 163 · see citing works
Hdmx protein stability is regulated by the ubiquitin ligase activity of Mdm2
de Graaf, P., Little, N. A., Ramos, Y. F. M., Meulmeester, E., Letteboer, S. J. F., & Jochemsen, A. G. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m213034200 · Cited by 143 · see citing works
Molecular Basis for the Inhibition of p53 by Mdmx
Popowicz, G. M., Czarna, A., Rothweiler, U., Szwagierczak, A., Krajewski, M., Weber, L., & Holak, T. A. (2007) · Cell Cycle · doi:10.4161/cc.6.19.4740 · Cited by 131 · see citing works
Fasan, R., Dias, R. L. A., Moehle, K., Zerbe, O., Obrecht, D., Mittl, P. R. E., Grütter, M. G., & Robinson, J. A. (2006) · ChemBioChem · doi:10.1002/cbic.200500452 · Cited by 129 · see citing works
Dastidar, S. G., Lane, D. P., & Verma, C. S. (2008) · Journal of the American Chemical Society · doi:10.1021/ja804289g · Cited by 87 · see citing works
Miniature Protein Inhibitors of the p53–hDM2 Interaction
Kritzer, J. A., Zutshi, R., Cheah, M. T., Ran, F. A., Webman, R. B., Wongjirad, T. M., & Schepartz, A. (2006) · ChemBioChem · doi:10.1002/cbic.200500324 · Cited by 87 · see citing works
Turning a Scorpion Toxin into an Antitumor Miniprotein
Li, C., Liu, M., Monbo, J., Zou, G., Li, C., Yuan, W., Zella, D., Lu, W., & Lu, W. (2008) · Journal of the American Chemical Society · doi:10.1021/ja8042036 · Cited by 75 · see citing works
Self-citationKallen, J. A., Goepfert, A., Blechschmidt, A., Izaac, A., Geiser, M., Tavares, G., Ramage, P., Furet, P., Masuya, K., & Lisztwan, J. H. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m809096200 · Cited by 72 · see citing works
Zondlo, S. C., Lee, A. E., & Zondlo, N. J. (2006) · Biochemistry · doi:10.1021/bi060309g · Cited by 65 · see citing works
Thermodynamics of p53 Binding to hdm2(1–126): Effects of Phosphorylation and p53 Peptide Length
Lai, Z., Auger, K. R., Manubay, C. M., & Copeland, R. A. (2000) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.2000.1998 · Cited by 64 · see citing works
Crystallographic Analysis of an 8-mer p53 Peptide Analogue Complexed with MDM2
Sakurai, K., Schubert, C., & Kahne, D. E. (2006) · Journal of the American Chemical Society · doi:10.1021/ja063102j · Cited by 58 · see citing works
Structure of Human MDM4 N-Terminal Domain Bound to a Single-Domain Antibody
Yu, G. W., Vaysburd, M., Allen, M. D., Settanni, G., & Fersht, A. R. (2008) · Journal of Molecular Biology · doi:10.1016/j.jmb.2008.11.043 · Cited by 12 · see citing works
Flagged first, then by citations
2 of the 53 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
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
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
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
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
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
Advance in peptide-based drug development: delivery platforms, therapeutics and vaccines
Xiao, W., Jiang, W., Chen, Z., Huang, Y., Mao, J., Zheng, W., Hu, Y., & Shi, J. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02107-5 · Cited by 449 · see citing works
The MDM2-p53 pathway revisited
Nag, S. A., Jiangjiang, Q., Kalkunte, S. S., Ming-hai, W., & Zhang, R. (2013) · Journal of Biomedical Research · doi:10.7555/jbr.27.20130030 · Cited by 414 · see citing works
Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
New Modalities for Challenging Targets in Drug Discovery
Valeur, E., Guéret, S. M., Adihou, H., Gopalakrishnan, R., Lemurell, M., Waldmann, H., Grossmann, T. N., & Plowright, A. T. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201611914 · Cited by 382 · see citing works
The Tumor Suppressor p53: From Structures to Drug DiscoveryPreprint
Joerger, A. C., & Fersht, A. R. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a000919 · Cited by 356 · see citing works
Targeting Transcription Factors for Cancer Treatment
Lambert, M., Jambon, S., Depauw, S., & David‐Cordonnier, M. (2018) · Molecules · doi:10.3390/molecules23061479 · Cited by 351 · see citing works
Peptide therapeutics: Targeting the undruggable space
Tsomaia, N. (2015) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2015.01.014 · Cited by 348 · see citing works
Gold nanoparticles functionalized with therapeutic and targeted peptides for cancer treatment
Kumar, A., Ma, H., Zhang, X., Huang, K., Jin, S., Liu, J., Wei, T., Cao, W., Zou, G., & Liang, X. (2011) · Biomaterials · doi:10.1016/j.biomaterials.2011.10.058 · Cited by 315 · see citing works
Self-citationThe 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 294 · see citing works
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 289 · see citing works
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 284 · see citing works
Structure of the Stapled p53 Peptide Bound to Mdm2
Baek, S., Kutchukian, P. S., Verdine, G. L., Huber, R., Holak, T. A., Lee, K. W., & Popowicz, G. M. (2012) · Journal of the American Chemical Society · doi:10.1021/ja2090367 · Cited by 259 · see citing works
Phage display—A powerful technique for immunotherapy
Bazan, J., Całkosiński, I., & Gamian, A. (2012) · Human Vaccines & Immunotherapeutics · doi:10.4161/hv.21703 · Cited by 253 · see citing works
p53-based Cancer TherapyPreprint
Lane, D. P., Cheok, C. F., & Laı́n, S. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a001222 · Cited by 244 · see citing works
In Vivo Activation of the p53 Tumor Suppressor Pathway by an Engineered Cyclotide
Ji, Y., Majumder, S., Millard, M., Borra, R., Bi, T., Elnagar, A. Y., Neamati, N., Shekhtman, A. G., & Camarero, J. A. (2013) · Journal of the American Chemical Society · doi:10.1021/ja405108p · Cited by 233 · see citing works
Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization
Graves, B., Thompson, T., Xia, M., Janson, C., Lukacs, C., Deo, D., Di Lello, P., Fry, D., Garvie, C., Huang, K.-S., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1203789109 · Cited by 230 · see citing works
p53 as a target for the treatment of cancer
Duffy, M. J., Synnott, N. C., McGowan, P. M., Crown, J. P., O’Connor, D. P., & Gallagher, W. M. (2014) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2014.10.004 · Cited by 230 · see citing works
Liu, M., Li, C., Pazgier, M., Li, C., Mao, Y., Lv, Y., Gu, B., Wei, G., Yuan, W., Zhan, C., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1008930107 · Cited by 229 · see citing works
Self-citationPhage Display in Molecular Imaging and Diagnosis of Cancer
Deutscher, S. L. (2010) · Chemical Reviews · doi:10.1021/cr900317f · Cited by 215 · see citing works
Stapled Peptides with Improved Potency and Specificity That Activate p53
Brown, C. J., Quah, S. T., Jong, J., Goh, A. M., Chiam, P. C., Khoo, K. H., Choong, M. L., Lee, M. A., Yurlova, L., Zolghadr, K., et al. (2012) · ACS Chemical Biology · doi:10.1021/cb3005148 · Cited by 206 · see citing works
Identification and Characterization of the First Small Molecule Inhibitor of MDMX
Reed, D., Shen, Y., Shelat, A. A., Arnold, L. A., Ferreira, A. M., Zhu, F., Mills, N., Smithson, D. C., Regni, C. A., Bashford, D., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.056747 · Cited by 198 · see citing works
Cardote, T. A. F., & Ciulli, A. (2015) · ChemMedChem · doi:10.1002/cmdc.201500450 · Cited by 189 · see citing works
Phan, J., Li, Z., Kasprzak, A., Li, B., Sebti, S., Guida, W., Schönbrunn, E., & Chen, J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.073056 · Cited by 173 · see citing works
The Structure‐Based Design of Mdm2/Mdmx–p53 Inhibitors Gets Serious
Popowicz, G. M., Dömling, A. S. S., & Holak, T. A. (2011) · Angewandte Chemie International Edition · doi:10.1002/anie.201003863 · Cited by 166 · see citing works
Protein-peptide association kinetics beyond the seconds timescale from atomistic simulations
Paul, F., Wehmeyer, C., Abualrous, E. T., Wu, H., Crabtree, M., Schöneberg, J., Clarke, J., Freund, C., Weikl, T. R., & Noé, F. (2017) · Nature Communications · doi:10.1038/s41467-017-01163-6 · Cited by 158 · see citing works
Antibody Engineering for Pursuing a Healthier Future
Saeed, A. F. U. H., Wang, R., Ling, S., & Wang, S. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.00495 · Cited by 154 · see citing works
Rational Design of Peptide-Based Inhibitors Disrupting Protein-Protein Interactions
Wang, X., Ni, D., Liu, Y., & Lu, S. (2021) · Frontiers in Chemistry · doi:10.3389/fchem.2021.682675 · Cited by 153 · see citing works
Targeting MDM2-p53 Interaction for Cancer Therapy: Are We There Yet?
Nag, S. A., Zhang, X., Srivenugopal, K. S., Wang, M.-H., Wang, W., & Zhang, R. (2014) · Current Medicinal Chemistry · doi:10.2174/09298673113206660325 · Cited by 151 · see citing works
Ultra-large chemical libraries for the discovery of high-affinity peptide binders
Quartararo, A. J., Gates, Z. P., Somsen, B. A., Hartrampf, N., Ye, X., Shimada, A., Kajihara, Y., Ottmann, C., & Pentelute, B. L. (2020) · Nature Communications · doi:10.1038/s41467-020-16920-3 · Cited by 154 · see citing works
Trapping Moving Targets with Small Molecules
Lee, G., & Craik, C. S. (2009) · Science · doi:10.1126/science.1169378 · Cited by 145 · see citing works
Systematic Mutational Analysis of Peptide Inhibition of the p53–MDM2/MDMX Interactions
Li, C. V., Pazgier, M., Li, C., Yuan, W., Liu, M., Wei, G., Lu, W., & Lu, W. (2010) · Journal of Molecular Biology · doi:10.1016/j.jmb.2010.03.005 · Cited by 146 · see citing works
Self-citationGuerlavais, V., Sawyer, T. K., Carvajal, L. A., Chang, Y. S., Graves, B. J., Ren, J.-G., Sutton, D., Olson, K. A., Packman, K. E., Darłak, K., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00623 · Cited by 145 · see citing works
Reactivation of p53: from peptides to small molecules
Brown, C. J., Cheok, C. F., Verma, C. S., & Lane, D. P. (2010) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2010.11.004 · Cited by 135 · see citing works
Yan, J., He, W., Yan, S., Niu, F., Liu, T., Ma, B., Shao, Y., Yan, Y., Yang, G., Lu, W., et al. (2018) · ACS Nano · doi:10.1021/acsnano.8b00081 · Cited by 133 · see citing works
Self-citationDouble Strain‐Promoted Macrocyclization for the Rapid Selection of Cell‐Active Stapled Peptides
Lau, Y. H., Wu, Y., Rossmann, M., Tan, B. X., de Andrade, P., Tan, Y. S., Verma, C. S., McKenzie, G. J., Venkitaraman, A. R., Hyvönen, M., et al. (2015) · Angewandte Chemie International Edition · doi:10.1002/anie.201508416 · Cited by 126 · see citing works
Lee, J. H., Zhang, Q., Jo, S., Chai, S. C., Oh, M., Im, W., Lu, H., & Lim, H. (2010) · Journal of the American Chemical Society · doi:10.1021/ja108230s · Cited by 126 · see citing works
Mirror-image protein and peptide drug discovery through mirror-image phage display
Qi, Y., Zheng, J., & Liu, L. (2024) · Chem · doi:10.1016/j.chempr.2024.06.004 · Cited by 122 · see citing works
Transient structure and dynamics in the disordered c-Myc transactivation domain affect Bin1 binding
Andrésen, C., Helander, S., Lemak, A. S., Farès, C., Csizmók, V., Carlsson, J., Penn, L. Z., Forman-Kay, J. D., Arrowsmith, C. H., Lundström, P., et al. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks263 · Cited by 119 · see citing works
A Left‐Handed Solution to Peptide Inhibition of the p53–MDM2 Interaction
Liu, M., Pazgier, M., Li, C., Yuan, W., Li, C., & Lu, W. (2010) · Angewandte Chemie International Edition · doi:10.1002/anie.201000329 · Cited by 115 · see citing works
Self-citationTargeting intrinsically disordered proteins involved in cancer
Santofimia‐Castaño, P., Rizzuti, B., Xia, Y., Abián, O., Peng, L., Velázquez‐Campoy, A., Neira, J. L., & Iovanna, J. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03347-3 · Cited by 110 · see citing works
Synthesis and applications of mirror-image proteins
Harrison, K., Mackay, A. S., Kambanis, L., Maxwell, J. W. C., & Payne, R. J. (2023) · Nature Reviews Chemistry · doi:10.1038/s41570-023-00493-y · Cited by 104 · see citing works
Estrada‐Ortiz, N., Neochoritis, C. G., & Dömling, A. S. S. (2015) · ChemMedChem · doi:10.1002/cmdc.201500487 · Cited by 100 · see citing works
Pelay‐Gimeno, M., Glas, A., Koch, O., & Grossmann, T. N. (2015) · Angewandte Chemie · doi:10.1002/ange.201412070 · Cited by 90 · see citing works
Liang, C., Yan, X., Zhang, R., Xu, T., Zheng, D., Tan, Z., Chen, Y., Gao, Z., Wang, L., Li, X., et al. (2019) · Journal of Controlled Release · doi:10.1016/j.jconrel.2019.11.028 · Cited by 89 · see citing works
Rational Improvement of the Affinity and Selectivity of Integrin Binding of Grafted Lasso Peptides
Hegemann, J. D., Simone, M. D., Zimmermann, M., Knappe, T. A., Xie, X., Leva, F. S. D., Marinelli, L., Novellino, E., Stefan Zahler, A., Kessler, H., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm5004478 · Cited by 89 · see citing works
Ma, B., Fan, Y., Zhang, D., Wei, Y., Jian, Y., Liu, D., Wang, Z., Gao, Y., Ma, J., Chen, Y., et al. (2022) · Advanced Science · doi:10.1002/advs.202201859 · Cited by 86 · see citing works
Ueda, T., Tamura, T., Kawano, M., Shiono, K., Hóbor, F., Wilson, A. J., & Hamachi, I. (2021) · Journal of the American Chemical Society · doi:10.1021/jacs.1c00703 · Cited by 84 · see citing works
Li, Y., Rodewald, L. W., Hoppmann, C., Wong, E. T., Lebreton, S., Šafář, P., Pátek, M., Wang, L., Wertman, K. F., & Wahl, G. M. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.10.058 · Cited by 83 · see citing works
Targeting p53-MDM2-MDMX Loop for Cancer Therapy
Zhang, Q., Zeng, S. X., & Lu, H. (2014) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-94-017-9211-0_16 · Cited by 83 · see citing works
Enhancing the Cell Permeability of Stapled Peptides with a Cyclic Cell-Penetrating Peptide
Dougherty, P. G., Wen, J., Pan, X., Koley, A., Ren, J.-G., Sahni, A., Basu, R., Salim, H., Kubi, G. A., Qian, Z., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00456 · Cited by 83 · see citing works
An Ultrahigh Affinity d -Peptide Antagonist Of MDM2
Zhan, C., Zhao, L., Wei, X., Wu, X., Chen, X., Yuan, W., Lu, W., Pazgier, M., & Lu, W. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm3005465 · Cited by 80 · see citing works
Self-citationIn-solution enrichment identifies peptide inhibitors of protein–protein interactions
Touti, F., Gates, Z. P., Bandyopadhyay, A., Lautrette, G., & Pentelute, B. L. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0245-2 · Cited by 81 · see citing works
Therapeutic stapled peptides: Efficacy and molecular targets
Li, Y., Wu, M., Fu, Y., Xue, J., Yuan, F., Qu, T., Rissanou, A. N., Wang, Y., Li, X., & Hu, H. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107137 · Cited by 85 · see citing works
Limitations of Peptide Retro-inverso Isomerization in Molecular Mimicry
Li, C., Pazgier, M., Li, J., Li, C., Liu, M., Zou, G., Li, Z., Chen, J., Tarasov, S. G., Lu, W., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.116814 · Cited by 79 · see citing works
Self-citationApamin as a Template for Structure‐Based Rational Design of Potent Peptide Activators of p53
Li, C., Pazgier, M., Liu, M., Lu, W., & Lu, W. (2009) · Angewandte Chemie International Edition · doi:10.1002/anie.200904550 · Cited by 79 · see citing works
Self-citationPeptidomimetics: A Synthetic Tool for Inhibiting Protein–Protein Interactions in Cancer
Mabonga, L., & Kappo, A. P. (2019) · International Journal of Peptide Research and Therapeutics · doi:10.1007/s10989-019-09831-5 · Cited by 78 · see citing works
Computed Binding of Peptides to Proteins with MELD-Accelerated Molecular Dynamics
Morrone, J. A., Pérez, A., MacCallum, J. L., & Dill, K. A. (2017) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.6b00977 · Cited by 75 · see citing works
Unnatural helical peptidic foldamers as protein segment mimics
Sang, P., & Cai, J. (2023) · Chemical Society Reviews · doi:10.1039/d2cs00395c · Cited by 76 · see citing works
Chen, J., Wang, J., Zhu, W., & Li, G. (2013) · Journal of Computer-Aided Molecular Design · doi:10.1007/s10822-013-9693-z · Cited by 75 · see citing works
Niu, F., Yan, J., Ma, B., Li, S., Shao, Y., He, P., Zhang, W., He, W., Ma, P. X., & Lu, W. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.03.025 · Cited by 72 · see citing works
Self-citationDithiocarbamate-inspired side chain stapling chemistry for peptide drug design
Li, X., Tolbert, W. D., Hu, H., Gohain, N., Zou, Y., Niu, F., He, W., Yuan, W., Su, J., Pazgier, M., et al. (2018) · Chemical Science · doi:10.1039/c8sc03275k · Cited by 71 · see citing works
Self-citationSharma, R., Borah, S. J., Bhawna, Kumar, S., Gupta, A., Singh, P., Goel, V. K., Kumar, R., & Kumar, V. (2022) · ACS Omega · doi:10.1021/acsomega.2c03974 · Cited by 71 · see citing works
Small molecules targeting protein–protein interactions for cancer therapy
Wu, D., Li, Y., Zheng, L., Xiao, H., Ouyang, L., Wang, G., & Sun, Q. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.05.035 · Cited by 71 · see citing works
Designing helical peptide inhibitors of protein–protein interactions
Araghi, R. R., & Keating, A. E. (2016) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2016.04.001 · Cited by 64 · see citing works
Interaction of regulators Mdm2 and Mdmx with transcription factors p53, p63 and p73
Zdzalik, M., Pustelny, K., Kędracka–Krok, S., Huben, K., Pęcak, A., Władyka, B., Jankowski, S., Dubin, A., Potempa, J., & Dubin, G. (2010) · Cell Cycle · doi:10.4161/cc.9.22.13871 · Cited by 65 · see citing works
Design of stapled peptide-based PROTACs for MDM2/MDMX atypical degradation and tumor suppression
Chen, S., Li, X., Li, Y., Xing, Y., Geng, C., Gao, S., Li, J., Ma, B., Wang, Z., Lu, W., et al. (2022) · Theranostics · doi:10.7150/thno.75444 · Cited by 64 · see citing works
Self-citationZhao, L., & Lu, W. (2014) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2014.09.019 · Cited by 62 · see citing works
Self-citationEnsemble-based virtual screening reveals dual-inhibitors for the p53–MDM2/MDMX interactions
Barakat, K., Mane, J. Y., Friesen, D. E., & Tuszyński, J. A. (2009) · Journal of Molecular Graphics and Modelling · doi:10.1016/j.jmgm.2009.12.003 · Cited by 61 · see citing works
Chen, X., Tai, L., Gao, J., Qian, J., Zhang, M., Li, B., Xie, C., Lu, L., Lu, W., & Lu, W. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.09.061 · Cited by 59 · see citing works
Self-citationExpanding the horizons of targeted protein degradation: A non-small molecule perspective
Huang, X., Wu, F., Ye, J., Wang, L., Wang, X., Li, X., & He, G. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.01.010 · Cited by 58 · see citing works
When the guardian sleeps: Reactivation of the p53 pathway in cancer
Merkel, O., Taylor, N., Prutsch, N., Staber, P. B., Moriggl, R., Turner, S. D., & Kenner, L. (2017) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2017.02.003 · Cited by 54 · see citing works
Targeting the Ubiquitin-Mediated Proteasome Degradation of p53 for Cancer Therapy
DeVine, T., & Dai, M. (2013) · Current Pharmaceutical Design · doi:10.2174/1381612811319180009 · Cited by 57 · see citing works
Partridge, A. W., Kaan, H. Y. K., Juang, Y.-C. A., Sadruddin, A., Lim, S., Brown, C. J., Ng, S., Thean, D., Ferrer, F. J., Johannes, C. W., et al. (2019) · Molecules · doi:10.3390/molecules24122292 · Cited by 57 · see citing works
On the Mechanism of Action of SJ-172550 in Inhibiting the Interaction of MDM4 and p53
Bista, M., Smithson, D., Pecak, A., Salinas, G., Pustelny, K., Min, J., Pirog, A., Finch, K., Zdzalik, M., Waddell, B., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037518 · Cited by 58 · see citing works
Wu, Y., Li, Y., Li, X., Zou, Y., Liao, H., Liu, L., Chen, Y., Bierer, D. E., & Hu, H. (2017) · Chemical Science · doi:10.1039/c7sc02420g · Cited by 56 · see citing works
Discovery of PSMA-specific peptide ligands for targeted drug delivery
Jin, W., Qin, B. Y., Chen, Z., Liu, H., Barve, A. J., & Cheng, K. (2016) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2016.08.048 · Cited by 55 · see citing works
Morrone, J. A., Pérez, A., Deng, Q., Ha, S., Holloway, M. K., Sawyer, T. K., Sherborne, B. S., Brown, F. K., & Dill, K. A. (2017) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.6b00978 · Cited by 54 · see citing works
Using Peptides to Study Protein–Protein Interactions
Benyamini, H., & Friedler, A. (2010) · Future Medicinal Chemistry · doi:10.4155/fmc.10.196 · Cited by 51 · see citing works
He, W., Yan, J., Sui, F., Wang, S., Su, X., Qu, Y., Yang, Q., Guo, H., Ji, M., Lu, W., et al. (2018) · ACS Nano · doi:10.1021/acsnano.8b07079 · Cited by 51 · see citing works
Self-citationA guide to the optogenetic regulation of endogenous molecules
Manoilov, K. Y., Verkhusha, V. V., & Shcherbakova, D. M. (2021) · Nature Methods · doi:10.1038/s41592-021-01240-1 · Cited by 51 · see citing works
Toxins and derivatives in molecular pharmaceutics: Drug delivery and targeted therapy
Zhan, C., Li, C., Wei, X., Lu, W., & Lu, W. (2015) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2015.04.025 · Cited by 49 · see citing works
Self-citationZhan, C., Varney, K. M., Yuan, W., Zhao, L., & Lu, W. (2012) · Journal of the American Chemical Society · doi:10.1021/ja301255n · Cited by 49 · see citing works
Self-citationChen, J., Wang, J., Zhang, Q., Chen, K., & Zhu, W. (2015) · Scientific Reports · doi:10.1038/srep17421 · Cited by 49 · see citing works
Target-Specific De Novo Peptide Binder Design with DiffPepBuilder
Wang, F., Wang, Y. X., Feng, L., Zhang, C., & Lai, L. (2024) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.4c00975 · Cited by 52 · see citing works
Casein Kinase 1α Regulates an MDMX Intramolecular Interaction To Stimulate p53 Binding
Wu, S., Chen, L., Becker, A., Schönbrunn, E., & Chen, J. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00851-12 · Cited by 48 · see citing works
Zhang, S., Lou, J., Li, Y., Zhou, F., Yan, Z., Lyu, X., & Zhao, Y. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00940 · Cited by 47 · see citing works
Lu, S., Wu, Y., Li, J., Meng, X., Hu, C., Zhao, Y., & Wu, C. (2020) · Journal of the American Chemical Society · doi:10.1021/jacs.0c06044 · Cited by 46 · see citing works
Self-citationCussol, L., Mauran, L., Buratto, J., Belorusova, A. Y., Neuville, M., Ősz, J., Fribourg, S., Frémaux, J., Dolain, C., Goudreau, S. R., et al. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202008992 · Cited by 46 · see citing works
Differences in the transactivation domains of p53 family members: a computational study
Mavinahalli, J., Madhumalar, A., Beuerman, R. W., Lane, D. P., & Verma, C. S. (2010) · BMC Genomics · doi:10.1186/1471-2164-11-s1-s5 · Cited by 46 · see citing works
Tackling Undruggable Targets with Designer Peptidomimetics and Synthetic Biologics
Swenson, C., Mandava, G., Thomas, D. M., & Moellering, R. E. (2024) · Chemical Reviews · doi:10.1021/acs.chemrev.4c00423 · Cited by 48 · see citing works
Zou, R., Zhou, Y., Wang, Y., Kuang, G., Ågren, H., Wu, J., & Tu, Y. (2020) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.9b00920 · Cited by 45 · see citing works
Recent Advances in Peptide-Based Approaches for Cancer Treatment
Conibear, A. C., Schmid, A., Kamalov, M., Becker, C. F. W., & Bello, C. (2017) · Current Medicinal Chemistry · doi:10.2174/0929867325666171123204851 · Cited by 44 · see citing works
Yan, J., Ji, F., Yan, S., You, W., Ma, F., Li, F., Huang, Y., Liu, W., & He, W. (2020) · Theranostics · doi:10.7150/thno.47243 · Cited by 44 · see citing works
Fujiwara, D., Kitada, H., Oguri, M., Nishihara, T., Michigami, M., Shiraishi, K., Yuba, E., Nakase, I., Im, H., Cho, S., et al. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201603230 · Cited by 44 · see citing works
- Authors
- Pazgier, M., Liu, M., Zou, G., Yuan, W., Li, C., Li, C., Li, J., Monbo, J., Zella, D., Tarasov, S. G., & Lu, W.
- Affiliations
- University of Maryland, Baltimore (US)
- National Cancer Institute (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-03-24
- Volume
- 106
- Issue
- 12
- Pages
- 4665-4670
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2660734
- OpenAlex
- W2076060796
- Cited by
- 391
- References
- 53
- Citations by year
- 2026: 10 · 2025: 28 · 2024: 27 · 2023: 23 · 2022: 18 · 2021: 29 · 2020: 25 · 2019: 24 · 2018: 18 · 2017: 31 · 2016: 18 · 2015: 20 · 2014: 24 · 2013: 21 · 2012: 19
- FWCI
- 12.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AI056264)
- National Institute of Allergy and Infectious Diseases (AI 061482, AI 056264, R21AI056264, R01AI061482)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- p53, MDM2, MDMX, peptide inhibitors, transactivation domain, crystal structure, hydrogen bond network, hydrophobic cleft, p53 activators, anticancer drug design, phage display peptide library, native chemical ligation
- MeSH terms
- Amino Acid Sequence, Humans, Models, Molecular, Molecular Sequence Data, Nuclear Proteins, Oligopeptides, Peptides, Protein Binding, Proto-Oncogene Proteins, Structure-Activity Relationship, Tumor Suppressor Protein p53, Protein Structure, Secondary, Cell Cycle Proteins, Peptide Library, Proto-Oncogene Proteins c-mdm2
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