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Protein–protein interactions as targets for small-molecule therapeutics in cancer

Published online by Cambridge University Press:  19 March 2008

Alex W. White ,
Andrew D. Westwell  and
Ghali Brahemi
Alex W. White*
Affiliation:
Welsh School of Pharmacy, King Edward VII Avenue, Cardiff University, Cardiff, CF10 3NB, UK.
Andrew D. Westwell
Affiliation:
Welsh School of Pharmacy, King Edward VII Avenue, Cardiff University, Cardiff, CF10 3NB, UK.
Ghali Brahemi
Affiliation:
Welsh School of Pharmacy, King Edward VII Avenue, Cardiff University, Cardiff, CF10 3NB, UK.
*
*Corresponding author: Alex W. White, Welsh School of Pharmacy, King Edward VII Avenue, Cardiff University, Cardiff, CF10 3NB, UK. Tel: +44 (0)29 2087 6308; Fax: +44 (0)29 2087 4149; E-mail: [email protected]
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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.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 10 , October 2008 , e8
Copyright
Copyright © Cambridge University Press 2008

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References

References

1Toogood, P.L. (2002) Inhibition of protein-protein association by small molecules: approaches and progress. J Med Chem 45, 1543-1558Google Scholar
2Sharma, S.K., Ramsey, T.M., and Bair, K.W. (2002) Protein-protein interactions: lessons learned. Curr Med Chem: Anticancer Agents 2, 311-330Google Scholar
3Arkin, M.R., and Wells, J.A. (2004) Small-molecule inhibitors of protein-protein interactions: Progressing towards the dream. Nat Rev Drug Discov 3, 301-317CrossRefGoogle ScholarPubMed
4Arkin, M. (2005) Protein-protein interactions and cancer: small molecules going in for the kill. Curr Opin Chem Biol 9, 317-324Google Scholar
5Fry, D.C. and Vassilev, L.T. (2005) Targeting protein-protein interactions for cancer therapy. J Mol Med 83, 955-963CrossRefGoogle ScholarPubMed
6Yin, H. and Hamilton, A.D. (2005) Strategies for targeting protein-protein interactions with synthetic agents. Angew Chem Int Ed Engl 44, 4130-4163Google Scholar
7Chene, P. (2006) Drugs targeting protein-protein interactions. Chem Med Chem 1, 400-411CrossRefGoogle ScholarPubMed
8Lindsley, C.W. (2007) Small molecule inhibition of protein-protein interaction: An emerging paradigm in drug design. Curr Top Med Chem 7, 921-921Google Scholar
9Wells, J.A. and McClendon, C.L. (2007) Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 450, 1001-1009Google Scholar
10Collins, I. and Workman, P. (2006) New approaches to molecular cancer therapeutics. Nat Chem Biol 2, 689-700Google Scholar
11Bogan, A.A. and Thorn, K.S. (1998) Anatomy of hot spots in protein interfaces. J Mol Biol 280, 1-9CrossRefGoogle ScholarPubMed
12Rudolph, J. (2007) Inhibiting transient protein-protein interactions: lessons from the Cdc25 protein tyrosine phosphatases. Nat Rev Cancer 7, 202-211CrossRefGoogle ScholarPubMed
13Zhong, S.J., Macias, A.T. and MacKerell, A.D. (2007) Computational identification of inhibitors of protein-protein interactions. Curr Top Med Chem 7, 63-82CrossRefGoogle ScholarPubMed
14Sundberg, E.J. and Mariuzza, R.A. (2000) Luxury accommodations: the expanding role of structural plasticity in protein-protein interactions. Structure 8, R137-R142Google Scholar
15Lo Conte, L., Chothia, C. and Janin, J. (1999) The atomic structure of protein-protein recognition sites. J Mol Biol 285, 2177-2198Google Scholar
16DeLano, W.L. (2002) Unraveling hot spots in binding interfaces: progress and challenges. Curr Opin Struct Biol 12, 14-20Google Scholar
17Sidhu, S.S., Fairbrother, W.J. and Deshayes, K. (2003) Exploring protein-protein interactions with phage display. Chembiochem 4, 14-25CrossRefGoogle ScholarPubMed
18Stites, W.E. (1997) Protein-protein interactions: Interface structure, binding thermodynamics, and mutational analysis. Chem Rev 97, 1233-1250CrossRefGoogle Scholar
19Nahta, R. and Esteva, F.J. (2006) Herceptin: mechanisms of action and resistance. Cancer Lett 232, 123-138CrossRefGoogle ScholarPubMed
20Downing, K.H. (2000) Structural basis for the interaction of tubulin with proteins and drugs that affect microtubules dynamics. Annu Rev Cell Dev Biol 16, 89-111CrossRefGoogle Scholar
21Jordan, M.A. (2002) Mechanism of action of antitumour drugs that interact with microtubules and tubulin. Curr Med Chem Anticancer Agents 2, 1-17Google Scholar
22Jordan, A. et al. (1998) Tubulin as a target for anticancer drugs: agents which interact with the mitotic spindle. Med Res Rev 18, 259-296Google Scholar
23Kavallaris, M., Verrills, N.M. and Hill, B.T. (2001) Anticancer therapy with novel tubulin interacting drugs. Drug Resist Updat 4, 392-401Google Scholar
24Nogales, E. (2001) Structural insights into microtubules function. Annu Rev Biophys Biomol Struct 30, 397-420Google Scholar
25Bollag, D.M. et al. (1995) Epothilones, a new class of microtubule-stabilizing agents with taxol-like mechanism of action. Cancer Res 55, 2325-2333Google ScholarPubMed
26Long, B.H. et al. (1998) Eleutherobin, a novel cytotoxic agent that induces tubulin polymerization, is similar to paclitaxel (Taxol®). Cancer Res 58, 1111-1115Google Scholar
27terHaar, E. et al. (1996) Discodermolide, a cytotoxic marine agent that stabilizes microtubules more potently than taxol. Biochemistry 35, 243-250Google Scholar
28Bai, R.L. et al. (1996) Identification of cysteine 354 of beta-tubulin as part of the binding site for the A ring of colchicine. J Biol Chem 271, 12639-12645CrossRefGoogle ScholarPubMed
29Uppuluri, S. et al. (1993) Localisation of the colchicine binding site of tubulin. Proc Natl Acad Sci U S A 90, 11539-11597Google Scholar
30Downing, K.H. and Nogales, E. (1998) New insights into microtubule structure and function from the atomic model of tubulin. Eur Biophys J Biophys Lett 27, 431-436Google Scholar
31Erickson, H.P. (1975) Negatively stained vinblastine aggregates. Proc Natl Acad Sci U S A 253, 51-52CrossRefGoogle ScholarPubMed
32Rai, S.S. and Wolff, J. (1996) Localization of the vinblastine-binding site on tubulin. J Biol Chem 271, 14707-14711Google Scholar
33Gupta, S. and Bhttacharyya, B. (2003) Antimicrotubule drugs binding to vinca domain of tubulin. Mol Cell Biochem 235, 41-47CrossRefGoogle Scholar
34Levin, A.J. (1997) p53, the cellular gatekeeper for growth and division. Cell 88, 323-331CrossRefGoogle Scholar
35Hollstein, M. et al. (1994) Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res 22, 3551-3555Google ScholarPubMed
36May, P. and May, E. (1999) Twenty years of p53 research: structural and functional aspects of the p53 protein. Oncogene 18, 7621-7636Google Scholar
37Bossi, G. and Sacchi, A. (2007) Restoration of wild-type p53 function in human cancer: relevance for tumour therapy. Head Neck 29, 272-284CrossRefGoogle Scholar
38Gudkov, A.V. and Kmarova, E.A. (2007) Dangerous habits of a security guard: The two faces of p53 as drug target. Hum Mol Genet 16, R62-R72CrossRefGoogle ScholarPubMed
39Lu, X. and Lane, D.P. (1993) Differential induction of transcriptionally active p53 following UV or ionizing radiation: defects in chromosome instability syndromes. Cell 75, 765-778CrossRefGoogle ScholarPubMed
40Clarke, A.R. et al. (1993) Thymocytes apoptosis induced by p53 dependent and independent pathways. Nature 362, 849-852CrossRefGoogle ScholarPubMed
41Yonish-Rouach, E. et al. (1994) Induction of apoptosis by transiently transfected metabolically stable wt p53 in transformed cell lines. Cell Death Differ 1, 39-47Google Scholar
42Wynford-Thomas, D. (1999) Cellular senescence and cancer. J Pathol 187, 100-1113.0.CO;2-T>CrossRefGoogle ScholarPubMed
43Wang, X.W. (1994) Hepatitis B virus X protein inhibits p53 sequence specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. Proc Natl Acad Sci U S A 91, 2230-2234Google Scholar
44Oren, M. (2003) Decision making by p53: life, death and cancer. Cell Death Differ 10, 431-442Google Scholar
45Marchenko, N.D., Zaika, A. and Moll, U.M. (2000) Death signal induced localization of p53 protein to mitochondria, a potential role in apoptotic signaling. J Biol Chem 275, 16202-16212Google Scholar
46Freedman, D.A., Wu, L. and Levine, A.J. (1999) Functions of the MDM2 oncoprotein. Cell Mol Life Sci 55, 96-107Google Scholar
47Wu, X. et al. (1993) The p53-mdm-2 autoregulatory feedback loop. Gene Dev 7, 1126-1132Google Scholar
48Fujiwara, T. et al. (1994) Therapeutic effect of a retroviral wild-type p53 expression vector in an orthotopic lung cancer model. J Natl Cancer Inst 86, 1458-1462Google Scholar
49Scardigli, R. et al. (1997) Expression of exogenous wt-p53 does not affect normal hematopoiesis: implications for bone marrow purging. Gene Ther 4, 1371-1378Google Scholar
50Vassilev, L.T. (2005) p53 activation by small molecules: application in oncology. J Med Chem 48, 4491-4499Google Scholar
51Kussie, P.H. et al. (1996) Crystal structure of the MDM2 oncoprotein bound to the transactivation domain of the p53 tumor suppressor. Science 274, 948-953Google Scholar
52Lin, J. et al. (1994) Functions of the p53 protein in growth regulation and tumor suppression. Cold Spring Harb Symp Quant Biol 59, 215-223Google Scholar
53Stoll, R. et al. (2001) Chalcone derivatives antagonize interactions between the human oncoprotein MDM2 and p53. Biochemistry 40, 336-344CrossRefGoogle ScholarPubMed
54Duncan, S.J. et al. (2001) Isolation and structure elucidation of chlorofusin, a novel p53-MDM2 antagonist from a Fusarium sp. J Am Chem Soc 123, 554-560Google Scholar
55Issaeva, N. et al. (2004) Small molecule RITA binds to p53, blocks p53 − HDM-2 interaction and activates p53 function in tumors. Nat Med 10, 1321-1328Google Scholar
56Grinkevich, V. et al. (2005) NMR indicates that the small molecule RITA does not block p53-MDM2 binding in vitro. Nat Med 11, 1135-1136Google Scholar
57Vassilev, L.T. et al. (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303, 844-848CrossRefGoogle ScholarPubMed
58Reed, J.C. (1998) Bcl-2 family proteins. Oncogene 17, 3225-3236Google Scholar
59Zornig, M. et al. (2001) Apoptosis regulators and their role in tumorigenesis. Biochim Biophys Acta Rev Cancer 1551, F1-F37Google Scholar
60Reed, J.C. (2002) Apoptosis-based therapies. Nat Rev Drug Discov 1, 111-121Google Scholar
61Borner, C. (2003) The Bcl-2 protein family: sensors and checkpoints for life-or-death decisions. Mol Immunol 39, 615-647Google Scholar
62van Delft, M.F. and Huang, D.C.S. (2006) How the Bcl-2 family of proteins interacts to regulate apoptosis. Cell Res 16, 203-213Google Scholar
63Wang, J.L. et al. (2000) Cell permeable Bcl-2 binding peptides: A chemical approach to apoptosis induction in tumour cells. Cancer Res 60, 1498-1502Google Scholar
64Sattler, M. et al. (1997) Structure of Bcl-x(L) Bak peptide complex: recognition between regulators of apoptosis. Science 275, 983-986Google Scholar
65Makin, G. and Dive, C. (2003) Recent advances in understanding apoptosis: new therapeutic opportunities in cancer chemotherapy. Trends Mol Med 9, 251-255Google Scholar
66Fesik, S.W. (2005) Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer 5, 876-885CrossRefGoogle ScholarPubMed
67Oltersdorf, T. et al. (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677-681Google Scholar
68Walensky, L.D. et al. (2004) Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 305, 1466-1470CrossRefGoogle ScholarPubMed
69Schimmer, A.D. (2004) Inhibitor of apoptosis proteins: translating basic knowledge into clinical practice. Cancer Res 64, 7183-7190CrossRefGoogle ScholarPubMed
70Deveraux, Q.L. et al. (1998) IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J 17, 2215-2223Google Scholar
71Chai, J. et al. (2001) Structural basis of caspase-7 inhibition by XIAP. Cell 104, 769-780Google Scholar
72Huang, Y.H. et al. (2001) Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain. Cell 104, 781-790Google Scholar
73Riedl, S.J. et al. (2001) Structural basis for the inhibition of caspase-3 by XIAP. Cell 104, 791-800Google Scholar
74Du, C.Y. et al. (2000) Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102, 33-42CrossRefGoogle ScholarPubMed
75Verhagen, A.M. et al. (2000) Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102, 43-53Google Scholar
76LaCasse, E.C. et al. (1998) The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene 17, 3247-3259Google Scholar
77Varfolomeev, E. et al. (2007) IAP antagonists induce autoubiquitination of c-IAPs, NF-κB activation, and TNFα-dependent apoptosis. Cell 131, 669-681Google Scholar
78Vince, J.E. et al. (2007) IAP antagonists target cIAP1 to induce TNFα-dependent apoptosis. Cell 131, 682-693Google Scholar
79Peterson, S.L. et al. (2007) Autocrine TNFα signalling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. Cancer Cell 12, 445-456Google Scholar
80Rajapakse, H.A. (2007) Small molecule inhibitors of the XIAP protein-protein interaction. Curr Top Med Chem 7, 966-971Google Scholar
81Hunter, A.M., LaCasse, E.C. and Korneluk, R.G. (2007) The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis 12, 1543-1568Google Scholar
82Oost, T.K. et al. (2004) Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer. J Med Chem 47, 4417-4426Google Scholar
83Feller, S.M and Lewitzky, M. (2006) Potential disease targets for drugs that disrupt protein-protein interactions of Grb2 and Crk family adaptors. Curr Pharm Design 12, 529-548Google Scholar
84Shakespeare, W.C. (2001) SH2 domain inhibition: a problem solved? Curr Opin Chem Biol 5, 409-415Google Scholar
85Furet, P. et al. (1998) Structure based design and synthesis of high affinity tripeptide ligands of the Grb2-SH2 domain. J Med Chem 41, 3442-3449Google Scholar
86Gao, Y. et al. (2000) Inhibition of Grb2 SH2 domain binding by non-phosphate containing ligands. 2. 4-(2-Malonyl)phenylalanine as a potent phosphotyrosyl mimetic. J Med Chem 43, 911-920Google Scholar
87de Vega, M.J.P., Martin-Martinez, M. and Gonzalez-Muniz, R. (2007) Modulation of protein-protein interactions by stabilizing/mimicking protein secondary structure elements. Curr Top Med Chem 7, 33-62Google Scholar
88Rahuel, J. et al. (1996) Structural basis for specificity of Grb2-SH2 revealed by a novel ligand binding mode. Nat Struct Biol 3, 586-589Google Scholar
89Gao, Y. et al. (2001) Macrocyclization in the design of a conformationally constrained Grb2-SH2 domain inhibitor. Bioorg Med Chem Lett 11, 1889-1892CrossRefGoogle ScholarPubMed
90Wei, C. et al. (2003) Macrocyclization in the design of Grb2-SH2 domain binding ligands exhibiting high potency in whole cell systems. J Med Chem 46, 244-254Google Scholar
91Walker, K. and Olson, M.F. (2005) Targeting Ras and Rho GTPases as opportunities for cancer therapeutics. Curr Opin Genet Dev 15, 62-68Google Scholar
92Waldmann, H. et al. (2004) Sulindac-derived Ras pathway inhibitors target the Ras-Raf interaction and downstream effectors in the Ras pathway. Angew Chem Int Ed Engl 43, 454-458Google Scholar
93Warne, P.H., Viciana, P.R. and Downward, J. (1993) Direct interaction of Ras and the amino-terminal region of Raf-1 in-vitro. Nature 364, 352-355CrossRefGoogle ScholarPubMed
94Barker, N. and Clevers, H. (2006) Mining the Wnt pathway for cancer therapeutics. Nat Rev Drug Discov 5, 997-1014Google Scholar
95Fujii, N. et al. (2007) An antagonist of dishevelled protein-protein interaction suppresses beta-catenin-dependent tumor cell growth. Cancer Res 67, 573-579Google Scholar
96Emami, K.H. et al. (2004) A small molecule inhibitor of beta-catenin/cyclic AMP response element-binding protein transcription. Proc Natl Acad Sci U S A 101, 12682-12687Google Scholar

Further reading, resources and contacts

For general information on all aspects of cancer (science, treatment and research) visit:

http://www.cancerresearchuk.org/Google Scholar
http://www.cancerhelp.org.uk/Google Scholar
http://www.rcsb.org/pdbGoogle Scholar
http://en.wikibooks.org/wiki/Proteomics/Protein_-_Protein_InteractionsGoogle Scholar
http://www.geminx.com (Phase 2 clinical trial of GX015-070 small-molecule BCL 2 inhibitor)Google Scholar
http://www.roche.com/ (Developing the p53–MDM2 inhibitors; detailed presentation at http://www.roche.com/med_mb200605lv.pdf)Google Scholar