Protein–protein interactions as targets for small-molecule therapeutics in cancer
Abstract
Small-molecule inhibition of the direct protein–protein interactions that mediate many important biological processes is an emerging and challenging area in drug design. Conventional drug design has mainly focused on the inhibition of a single protein, usually an enzyme or receptor, since these proteins often contain a clearly defined ligand-binding site with which a small-molecule drug can be designed to interact. Designing a small molecule to bind to a protein–protein interface and subsequently inhibit the interaction poses several challenges, including the initial identification of suitable protein–protein interactions, the surface area of the interface (it is often large), and the location of ‘hot spots’ (small regions suitable for drug binding). This article reviews the general approach to designing inhibitors of protein–protein interactions, and then focuses on recent advances in the use of small molecules targeted against a variety of protein–protein interactions that have therapeutic potential for cancer.
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Abnormalities in PPIs can result in various diseases, such as cancers, infectious diseases, and neurodegenerative diseases.
“However, abnormalities in PPIs can result in a various diseases, such as cancers, infectious diseases, and neurodegenerative diseases.306–308”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [306]
Cites
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
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
Du, C., Fang, M., Li, Y., Li, L., & Wang, X. (2000) · Cell · doi:10.1016/s0092-8674(00)00008-8 · Cited by 3,513 · see citing works
An inhibitor of Bcl-2 family proteins induces regression of solid tumours
Oltersdorf, T., Elmore, S. W., Shoemaker, A. R., Armstrong, R. C., Augeri, D. J., Belli, B., Bruncko, M., Deckwerth, T. L., Dinges, J., Hajduk, P. J., et al. (2005) · Nature · doi:10.1038/nature03579 · Cited by 3,407 · see citing works
Verhagen, A. M., Ekert, P. G., Pakusch, M., Silke, J., Connolly, L. M., Reid, G. E., Moritz, R. L., Simpson, R. J., & Vaux, D. L. (2000) · Cell · doi:10.1016/s0092-8674(00)00009-x · Cited by 2,372 · see citing works
Thymocyte apoptosis induced by p53-dependent and independent pathways
Clarke, A. R., Purdie, C. A., Harrison, D. J., Morris, R. G., Bird, C. C., Hooper, M. L., & Wyllie, A. H. (1993) · Nature · doi:10.1038/362849a0 · Cited by 2,271 · 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
Anatomy of hot spots in protein interfaces
Bogan, A. A., & Thorn, K. S. (1998) · Journal of Molecular Biology · doi:10.1006/jmbi.1998.1843 · Cited by 1,988 · see citing works
The atomic structure of protein-protein recognition sites 1 1Edited by A. R. Fersht
Conte, L. L., Chothia, C., & Janin, J. (1999) · Journal of Molecular Biology · doi:10.1006/jmbi.1998.2439 · Cited by 1,967 · 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
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
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
Structure of Bcl-x <sub>L</sub> -Bak Peptide Complex: Recognition Between Regulators of Apoptosis
Sattler, M., Liang, H., Nettesheim, D., Meadows, R. P., Harlan, J. E., Eberstadt, M., Yoon, H. S., Shuker, S. B., Chang, B. S., Minn, A. J., et al. (1997) · Science · doi:10.1126/science.275.5302.983 · Cited by 1,476 · see citing works
Deveraux, Q. L., Roy, N., Stennicke, H. R., Arsdale, T. V., Zhou, Q., Srinivasula, S. M., Alnemri, E. S., Salvesen, G. S., & Reed, J. C. (1998) · The EMBO Journal · doi:10.1093/emboj/17.8.2215 · Cited by 1,390 · see citing works
Activation of Apoptosis in Vivo by a Hydrocarbon-Stapled BH3 Helix
Walensky, L. D., Kung, A. L., Escher, I., Malia, T. J., Barbuto, S., Wright, R. D., Wagner, G., Verdine, G. L., & Korsmeyer, S. J. (2004) · Science · doi:10.1126/science.1099191 · Cited by 1,349 · see citing works
IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB Activation, and TNFα-Dependent Apoptosis
Varfolomeev, E., Blankenship, J. W., Wayson, S. M., Fedorova, A. V., Kayagaki, N., Garg, P., Zobel, K., Dynek, J. N., Elliott, L. O., Wallweber, H. J. A., et al. (2007) · Cell · doi:10.1016/j.cell.2007.10.030 · Cited by 1,218 · 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
Decision making by p53: life, death and cancer
Oren, M. (2003) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401183 · Cited by 1,063 · see citing works
IAP Antagonists Target cIAP1 to Induce TNFα-Dependent Apoptosis
Vince, J. E., Wong, W. W.-L., Khan, N. R., Feltham, R., Chau, D., Ahmed, A. U., Benetatos, C. A., Chunduru, S. K., Condon, S. M., McKinlay, M. A., et al. (2007) · Cell · doi:10.1016/j.cell.2007.10.037 · Cited by 1,061 · see citing works
Reed, J. C. (1998) · Oncogene · doi:10.1038/sj.onc.1202591 · Cited by 1,057 · see citing works
The inhibitors of apoptosis (IAPs) and their emerging role in cancer
LaCasse, E. C., Baird, S. D., Korneluk, R. G., & MacKenzie, A. (1998) · Oncogene · doi:10.1038/sj.onc.1202569 · Cited by 980 · see citing works
Death Signal-induced Localization of p53 Protein to Mitochondria
Marchenko, N. D., Zaika, A. I., & Moll, U. M. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.21.16202 · Cited by 902 · see citing works
A small molecule inhibitor of β-catenin/cyclic AMP response element-binding protein transcription
Emami, K. H., Nguyen, C., Ma, H., Kim, D. H., Jeong, K. W., Eguchi, M., Moon, R. T., Teo, J.-L., Oh, S. W., Kim, H. Y., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404875101 · Cited by 879 · see citing works
Database of p53 gene somatic mutations in human tumors and cell lines.
Hollstein, M. C., Rice, K., Greenblatt, M. S., Soussi, T., Fuchs, R., Sørlie, T., Hovig, E. J., Smith‐Sørensen, B., Montesano, R., & Harris, C. C. (1994) · Europe PMC (PubMed Central) · Cited by 860 · see citing works
Structural Basis for the Inhibition of Caspase-3 by XIAP
Riedl, S. J., Renatus, M., Schwarzenbacher, R., Zhou, Q., Sun, C. C., Fesik, S. W., Liddington, R., & Salvesen, G. S. (2001) · Cell · doi:10.1016/s0092-8674(01)00274-4 · Cited by 793 · see citing works
Mechanism of Action of Antitumor Drugs that Interact with Microtubules and Tubulin
Jordan, M. A. (2005) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/1568011023354290 · Cited by 776 · see citing works
Unraveling hot spots in binding interfaces: progress and challenges
DeLano, W. L. (2002) · Current Opinion in Structural Biology · doi:10.1016/s0959-440x(02)00283-x · Cited by 767 · 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
Mining the Wnt pathway for cancer therapeutics
Barker, N., & Clevers, H. C. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2154 · Cited by 746 · see citing works
Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro
Warne, P. H., Vician, P. R., & Downward, J. (1993) · Nature · doi:10.1038/364352a0 · Cited by 729 · see citing works
The Bcl-2 protein family: sensors and checkpoints for life-or-death decisions
Borner, C. (2002) · Molecular Immunology · doi:10.1016/s0161-5890(02)00252-3 · Cited by 700 · see citing works
Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action.
Bollag, D. M., McQueney, P. A., Zhu, J., Hensens, O. D., Koupal, L. R., Liesch, J. M., Goetz, M., Lazarides, E., & Woods, C. M. (1995) · PubMed · Cited by 687 · see citing works
Tubulin as a target for anticancer drugs: Agents which interact with the mitotic spindle
Jordan, A. M., Hadfield, J. A., Lawrence, N. J., & McGown, A. T. (1998) · Medicinal Research Reviews · doi:10.1002/(sici)1098-1128(199807)18:4 · Cited by 671 · see citing works
Wang, X. W., Forrester, K., Yeh, H., Feitelson, M. A., Gu, J., & Harris, C. C. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.6.2230 · Cited by 666 · see citing works
Twenty years of p53 research: structural and functional aspects of the p53 protein
May, P., & May, E. (1999) · Oncogene · doi:10.1038/sj.onc.1203285 · Cited by 663 · see citing works
Reed, J. C. (2002) · Nature Reviews Drug Discovery · doi:10.1038/nrd726 · Cited by 640 · see citing works
Structural Basis of Caspase-7 Inhibition by XIAP
Chai, J., Shiozaki, E. N., Srinivasula, S. M., Wu, Q. Y., Dataa, P., Alnemri, E. S., & Shi, Y. (2001) · Cell · doi:10.1016/s0092-8674(01)00272-0 · Cited by 582 · see citing works
Functions of the MDM2 oncoprotein
Freedman, D. A., Wu, L., & Levine, A. J. (1999) · Cellular and Molecular Life Sciences · doi:10.1007/s000180050273 · Cited by 573 · see citing works
Autocrine TNFα Signaling Renders Human Cancer Cells Susceptible to Smac-Mimetic-Induced Apoptosis
Petersen, S. L., Wang, L., Yalcin-Chin, A., Li, L., Peyton, M., Minna, J. D., Harran, P. G., & Wang, X. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.08.029 · Cited by 572 · see citing works
The inhibitors of apoptosis (IAPs) as cancer targets
Hunter, A. M., LaCasse, E. C., & Korneluk, R. G. (2007) · Apoptosis · doi:10.1007/s10495-007-0087-3 · Cited by 565 · see citing works
Inhibitor of Apoptosis Proteins: Translating Basic Knowledge into Clinical Practice
Schimmer, A. D. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1918 · Cited by 513 · see citing works
Protein−Protein Interactions: Interface Structure, Binding Thermodynamics, and Mutational Analysis
Stites, W. E. (1997) · Chemical Reviews · doi:10.1021/cr960387h · Cited by 491 · see citing works
Structural Basis of Caspase Inhibition by XIAP
Huang, Y., Park, Y. C., Rich, R. L., Segal, D., Myszka, D. G., & Wu, H. (2001) · Cell · doi:10.1016/s0092-8674(01)00273-2 · Cited by 480 · see citing works
Strategies for Targeting Protein–Protein Interactions With Synthetic Agents
Yin, H. H., & Hamilton, A. D. (2005) · Angewandte Chemie International Edition · doi:10.1002/anie.200461786 · Cited by 453 · see citing works
Herceptin: mechanisms of action and resistance
Nahta, R., & Esteva, F. J. (2005) · Cancer Letters · doi:10.1016/j.canlet.2005.01.041 · Cited by 446 · see citing works
New approaches to molecular cancer therapeutics
Collins, I., & Workman, P. (2006) · Nature Chemical Biology · doi:10.1038/nchembio840 · Cited by 390 · see citing works
Downing, K. H. (2000) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.16.1.89 · Cited by 383 · see citing works
ter Haar, E., Kowalski, R. J., Hamel, E., Lin, C. M., Longley, R. E., Gunasekera, S. P., Rosenkranz, H. S., & Day, B. W. (1996) · Biochemistry · doi:10.1021/bi9515127 · Cited by 382 · see citing works
Structural Insights into Microtubule Function
Nogales, E. (2001) · Annual Review of Biophysics and Biomolecular Structure · doi:10.1146/annurev.biophys.30.1.397 · Cited by 378 · see citing works
Discovery of Potent Antagonists of the Antiapoptotic Protein XIAP for the Treatment of Cancer
Oost, T. K., Sun, C. C., Armstrong, R. C., Al-Assaad, A.-S., Betz, S. F., Deckwerth, T. L., Ding, H., Elmore, S. W., Meadows, R. P., Olejniczak, E. T., et al. (2004) · Journal of Medicinal Chemistry · doi:10.1021/jm040037k · Cited by 367 · see citing works
How the Bcl-2 family of proteins interact to regulate apoptosis
van Delft, M. F., & Huang, D. C. S. (2006) · Cell Research · doi:10.1038/sj.cr.7310028 · Cited by 335 · see citing works
Inhibition of Protein−Protein Association by Small Molecules: Approaches and Progress
Toogood, P. L. (2002) · Journal of Medicinal Chemistry · doi:10.1021/jm010468s · Cited by 281 · see citing works
Chalcone Derivatives Antagonize Interactions between the Human Oncoprotein MDM2 and p53
Stoll, R., Renner, C., Hansen, S., Palme, S., Klein, C., Belling, A., Żesławski, W., Kamionka, M., Rehm, T., Mühlhahn, P., et al. (2000) · Biochemistry · doi:10.1021/bi000930v · Cited by 275 · see citing works
Apoptosis regulators and their role in tumorigenesis
Zörnig, M., Hueber, A., Baum, W., & Evan, G. I. (2001) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/s0304-419x(01)00031-2 · Cited by 239 · see citing works
Structural basis for specificity of GRB2-SH2 revealed by a novel ligand binding mode
Rahuel, J., Gay, B., Erdmann, D., et al. (1996) · Nature Structural Biology · doi:10.1038/nsb0796-586 · Cited by 236 · see citing works
Huang, Y. (2001) · Cell · doi:10.1016/s0092-8674(02)02075-5 · Cited by 233 · see citing works
Fujii, N., You, L., Xu, Z., Uematsu, K., Shan, J., He, B., Mikami, I., Edmondson, L. R., Neale, G. A. M., Zheng, J., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-2726 · Cited by 232 · see citing works
Long, B. H., Carboni, J. M., Wasserman, A. J., et al. (1998) · PubMed · Cited by 222 · see citing works
Fujiwara, T., Cai, D. W., Georges, R. N., et al. (1994) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/86.19.1458 · Cited by 220 · see citing works
Exploring Protein–Protein Interactions with Phage Display
Sidhu, S. S., Fairbrother, W. J., & Deshayes, K. (2003) · ChemBioChem · doi:10.1002/cbic.200390008 · Cited by 189 · see citing works
Protein–protein interactions and cancer: small molecules going in for the kill
Arkin, M. R. (2005) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2005.03.001 · Cited by 176 · see citing works
p53 Activation by Small Molecules: Application in Oncology
Vassilev, L. T. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm058174k · Cited by 172 · see citing works
Isolation and Structure Elucidation of Chlorofusin, a Novel p53-MDM2 Antagonist from a Fusarium sp.
Duncan, S. J., Grüschow, S., Williams, D. H., McNicholas, C., Purewal, R., Hájek, M., Gerlitz, M., Martin, S., Wrigley, S. K., & Moore, M. (2001) · Journal of the American Chemical Society · doi:10.1021/ja002940p · Cited by 171 · see citing works
Cell permeable Bcl-2 binding peptides: a chemical approach to apoptosis induction in tumor cells.
Wang, J., Zhang, Z. J., Choksi, S., et al. (2000) · PubMed · Cited by 168 · see citing works
Localization of the Vinblastine-binding Site on β-Tubulin
Rai, S. S., & Wolff, J. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.25.14707 · Cited by 166 · see citing works
Localization of the colchicine-binding site of tubulin.
Uppuluri, S., Knipling, L., Sackett, D. L., et al. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.24.11598 · Cited by 161 · see citing works
Identification of Cysteine 354 of β-Tubulin as Part of the Binding Site for the A Ring of Colchicine
Bai, R., Pei, X., Boyé, O., et al. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.21.12639 · Cited by 159 · see citing works
Targeting protein–protein interactions for cancer therapy
Fry, D. C., & Vassilev, L. T. (2005) · Journal of Molecular Medicine · doi:10.1007/s00109-005-0705-x · Cited by 156 · see citing works
Anticancer therapy with novel tubulin-interacting drugs
Kavallaris, M., Verrills, N. M., & Hill, B. T. (2001) · Drug Resistance Updates · doi:10.1054/drup.2002.0230 · Cited by 129 · see citing works
Drugs Targeting Protein–Protein Interactions
Chêne, P. (2006) · ChemMedChem · doi:10.1002/cmdc.200600004 · Cited by 129 · see citing works
Targeting Ras and Rho GTPases as opportunities for cancer therapeutics
Walker, K. M., & Olson, M. F. (2004) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2004.11.001 · Cited by 125 · see citing works
NMR indicates that the small molecule RITA does not block p53-MDM2 binding in vitro
Krajewski, M., Ozdowy, P., D’Silva, L., Rothweiler, U., & Holak, T. A. (2005) · Nature Medicine · doi:10.1038/nm1105-1135 · Cited by 96 · see citing works
de Vega, M. J. P., Martín‐Martinez, M., & González‐Muñiz, R. (2006) · Current Topics in Medicinal Chemistry · doi:10.2174/156802607779318325 · Cited by 90 · see citing works
Restoration of wild‐type p53 function in human cancer: Relevance for tumor therapy
Bossi, G., & Sacchi, A. (2007) · Head & Neck · doi:10.1002/hed.20529 · Cited by 87 · see citing works
Computational Identification of Inhibitors of Protein-Protein Interactions
Zhong, S., Macias, A. T., & MacKerell, A. D. (2006) · Current Topics in Medicinal Chemistry · doi:10.2174/156802607779318334 · Cited by 84 · see citing works
Structure-Based Design and Synthesis of High Affinity Tripeptide Ligands of the Grb2-SH2 Domain
Furet, P., Gay, B., Caravatti, G., Garcı́a-Echeverrı́a, C., Rahuel, J., Schoepfer, J. G., & Fretz, H. (1998) · Journal of Medicinal Chemistry · doi:10.1021/jm980159a · Cited by 83 · see citing works
Waldmann, H., Karaguni, I., Carpintero, M., Gourzoulidou, E., Herrmann, C., Brockmann, C., Oschkinat, H., & Müller, O. (2004) · Angewandte Chemie International Edition · doi:10.1002/anie.200353089 · Cited by 83 · see citing works
SH2 domain inhibition: a problem solved?
Shakespeare, W. C. (2001) · Current Opinion in Chemical Biology · doi:10.1016/s1367-5931(00)00222-2 · Cited by 82 · see citing works
Luxury accommodations: the expanding role of structural plasticity in protein–protein interactions
Sundberg, E. J., & Mariuzza, R. A. (2000) · Structure · doi:10.1016/s0969-2126(00)00167-2 · Cited by 81 · see citing works
Rudolph, J. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2087 · Cited by 79 · see citing works
Dangerous habits of a security guard: the two faces of p53 as a drug target
Gudkov, A. V., & Komarova, E. A. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm052 · Cited by 67 · see citing works
New insights into microtubule structure and function from the atomic model of tubulin
Downing, K. H., & Nogales, E. (1998) · European Biophysics Journal · doi:10.1007/s002490050153 · Cited by 66 · see citing works
Antimicrotubular drugs binding to vinca domain of tubulin
Gupta, S., & Bhattacharyya, B. (2003) · Molecular and Cellular Biochemistry · doi:10.1023/a:1026045100219 · Cited by 64 · see citing works
Gao, Y., Luo, J. H., Yao, Z.-J., et al. (2000) · Journal of Medicinal Chemistry · doi:10.1021/jm9904248 · Cited by 57 · see citing works
NEGATIVELY STAINED VINBLASTINE AGGREGATES
Erickson, H. (1975) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1975.tb19191.x · Cited by 43 · see citing works
Feller, S. M., & Lewitzky, M. (2006) · Current Pharmaceutical Design · doi:10.2174/138161206775474369 · Cited by 42 · see citing works
Wei, C.-Q., Gao, Y., Lee, K., Guo, R., Li, B., Zhang, M., Yang, D., & Burke, T. R. (2002) · Journal of Medicinal Chemistry · doi:10.1021/jm0203635 · Cited by 41 · see citing works
Protein-Protein Interactions: Lessons Learned
Sharma, S., Ramsey, T. M., & Bair, K. W. (2002) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/1568011023354191 · Cited by 37 · see citing works
Recent advances in understanding apoptosis: new therapeutic opportunities in cancer chemotherapy
Makin, G., & Dive, C. (2003) · Trends in Molecular Medicine · doi:10.1016/s1471-4914(03)00084-4 · Cited by 35 · see citing works
Macrocyclization in the design of a conformationally constrained Grb2 SH2 domain inhibitor
Gao, Y., Voigt, J. H., Wu, J. X., et al. (2001) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/s0960-894x(01)00316-x · Cited by 34 · see citing works
Functions of the p53 Protein in Growth Regulation and Tumor SuppressionPreprint
Lin, J., Wu, X., Chen, J., Chang, A., & Levine, A. J. (1994) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.1994.059.01.026 · Cited by 32 · see citing works
Yonish-Rouach, E., Borde, J., Gotteland, M., Mishal, Z., Viron, A., & May, E. (1994) · PubMed · Cited by 30 · see citing works
Scardigli, R., Bossi, G., Blandino, G., et al. (1997) · Gene Therapy · doi:10.1038/sj.gt.3300530 · Cited by 21 · see citing works
Small Molecule Inhibitors of the XIAP Protein-Protein Interaction
Rajapakse, H. A. (2007) · Current Topics in Medicinal Chemistry · doi:10.2174/156802607780906816 · Cited by 20 · see citing works
Reply to 'NMR indicates that the small molecule RITA does not block p53-MDM2 binding in vitro'
Grinkevich, V. V., Issaeva, N., Hossain, S., et al. (2005) · Nature Medicine · doi:10.1038/nm1105-1136 · Cited by 12 · see citing works
Drugs Targeting Protein–Protein Interactions
Chêne, P. (2007) · Chemical biology · doi:10.1002/9783527619375.ch15e · Cited by 12 · see citing works
Lindsley, C. W. (2007) · Current Topics in Medicinal Chemistry · doi:10.2174/156802607780906780 · Cited by 2 · see citing works
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- Authors
- White, A. W., Westwell, A. D., & Brahemi, G.
- Affiliations
- Cardiff University (GB)
- Corresponding author
- White, Alex W.
- Venue
- Expert Reviews in Molecular Medicine
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- Cambridge University Press (CUP)
- Published
- 2008-03
- Volume
- 10
- Pages
- e8-e8
- ISSN
- 1462-3994 (ISSN-L)
- OpenAlex
- W2161203845
- Cited by
- 122
- References
- 99
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- FWCI
- 0.57
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- journal article
- Language
- en
- Open access
- closed
- Locations
- Expert Reviews in Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- protein-protein interaction, small molecule inhibitors, cancer therapeutics, drug design, protein-protein interfaces, hot spots
- MeSH terms
- Animals, Antineoplastic Agents, Binding Sites, Enzyme Inhibitors, Humans, Ligands, Neoplasms, Protein Binding, Proteins, Surface Properties, Biomarkers, Tumor, Drug Design, Signal Transduction
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 ›
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