Abstract
An increasing number of protein–protein interactions have been identified as potential intervention points for the development of anticancer agents. However, such systems have historically been considered high-risk targets due to the relatively large interaction surfaces involved in protein–protein binding. This characterization has to be reexamined as progress has been made recently in identifying small-molecule inhibitors of several protein–protein systems in oncology including the p53–MDM2 interaction. This review presents a survey of protein–protein interactions that have been identified as potential oncology targets and evaluates their attractiveness in terms of drug discovery. The analysis focuses primarily on the structural characteristics of the participating binding sites, particularly the dimensions of the sites. Known ligands are also examined, especially with regard to their druglikeness.
Similar content being viewed by others
References
Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu E (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303:844–848
Clackson T, Wells JA (1995) A hot spot of binding energy in a hormone–receptor interface. Science 267:383–386
Toogood PL (2002) Inhibition of protein–protein association by small molecules: approaches and progress. J Med Chem 45:1543–1558
Berg T (2003) Modulation of protein–protein interactions with small organic molecules. Angew Chem Int Ed Engl 42:2462–2481
Arkin MR, Wells JA (2004) Small-molecule inhibitors of protein–protein interactions: progressing towards the dream. Nat Rev Drug Discov 3:301–317
McDowell RS, Blackburn BK, Gadek TR, McGee LR, Rawson T, Reynolds ME, Robarge KD, Somers TC, Thorsett ED, Tischler M, Webb RR, Venuti MC (1994) From peptide to non-peptide. 2. The de novo design of potent, non-peptidal inhibitors of platelet aggregation based on a benzodiazepine scaffold. J Am Chem Soc 116:5077–5083
Ku TW, Ali FE, Barton, LS, Bean JW, Bondinell WE, Burgess JL, Callahan JF, Calvo RR, Chen L, Eggleston DS, Gleason JG, Huffman WF, Hwang SM, Jakas DR, Karash CB, Keenan RM, Kopple KD, Miller WH, Newlander KA, Nichols A, Parker MF, Peishoff CE, Samanen JM, Uzinskas I, Venslavsky JW (1993) Direct design of a potent non-peptide fibrinogen receptor antagonist based on the structure and conformation of a highly constrained cyclic RGD peptide. J Am Chem Soc 115:8861–8862
Stahl M, Bur D, Schneider G (1999) Mapping of proteinase active sites by projection of surface-derived correlation vectors. J Comput Chem 20:336–347
Graham TA, Weaver C, Mao F, Kimelman D, Xu W (2000) Crystal structure of a beta-catenin/Tcf complex. Cell 103:885–896
Zheng N, Schulman BA, Song L, Miller JJ, Jeffrey PD, Wang P, Chu C, Koepp DM, Elledge SJ, Pagano M, Conaway RC, Conaway JW, Harper JW, Pavletich NP (2002) Structure of the Cul1–Rbx1–Skp1–F box(Skp2) SCF ubiquitin ligase complex. Nature 416:703–709
Emerson SD, Madison VS, Palermo RE, Waugh DS, Scheffler JE, Tsao K-L, Kiefer SE, Liu SP, Fry DC (1995) Solution structure of the ras-binding domain of c-raf-1 and identification of its ras interaction surface. Biochemistry 34:6911–6918
Nassar N, Horn G, Herrmann C, Scherer A, McCormick F, Wittinghofer A (1995) The 2.2 angstrom crystal structure of the ras-binding domain of the serine/threonine kinase c-raf-1 in complex with rap-1a and a GTP analog. Nature 375:554–560
Zhao X, Ghaffari S, Lodish H, Malashkevich VN, Kim PS (2002) Nat Struct Biol 9:117–120
Tong L, Warren TC, King J, Betageri R, Rose J, Jakes S (1996) Crystal structures of the human p56lck SH2 domain in complex with two short phosphotyrosyl peptides at 1.0 A and 1.8 A resolution. J Mol Biol 256:601–610
Elia AEH, Rellos P, Haire LF, Chao JW, Ivins FJ, Hoepker K, Mohammad D, Cantley LC, Smerdon SJ, Yaffe MB (2003) The molecular basis for phosphodependent substrate targeting and regulation of Plks by the Polo Box domain. Cell 115:83–95
Chen X, Bhandari R, Vinkemeier U, Van Den Akker F, Darnell JE, Kuriyan J (2003) A reinterpretation of the dimerization interface of the N-terminal domains of Stats. Protein Sci 12:361–365
Dames SA, Martinez-Yamout M, De Guzman RN, Dyson HJ, Wright PE (2002) Structural basis for Hif-1alpha/CBP recognition in the cellular hypoxic response. Proc Natl Acad Sci U S A 99:5271–5276
Himane JP, Rajashankar KR, Lackman M, Cowan CA, Henkemeyer M, Nikolov DB (2001) Crystal structure of an Eph receptor–ephrin complex. Nature 414:933–938
Rustandi RR, Baldisseri DM, Weber DJ (2000) Solution structure of the C-terminal negative regulatory domain of p53 bound to S100B(Bb). Nat Struct Biol 7:570–574
Markowitz J, Chen I, Gitti R, Baldisseri DM, Pan Y, Udan R, Carrier F, MacKerell AD, Weber D (2004) Identification and characterization of small molecule inhibitors of the calcium-dependent S100B–p53 tumor suppressor interaction. J Med Chem 47:5085–5093
Sattler M, Liang H, Nettesheim D, Meadows RP, Harlan JE, Eberstadt M, Yoon HS, Shuker SB, Chang BS, Minn AJ, Thompson CB, Fesik SW (1997) Structure of Bcl-XL–Bak peptide complex: recognition between regulators of apoptosis. Science 275:983–986
Kim KM, Giedt CD, Basanez G, O’Neill JW, Hill JJ, Han YH, Tzung SP, Zimmerberg J, Hockenbery DM, Zhang KYJ (2001) Biophysical characterization of recombinant human Bcl-2 and its interactions with an inhibitory ligand. Biochemistry 40:4911–4922
Nakashima T, Miura M, Hara M (2000) Tetrocardin A inhibits mitochondrial functions of Bcl-2 and suppresses its anti-apoptotic activity. Cancer Res 60:1229–1235
Chan SL, Lee MC, Tan KO, Yang LK, Lee ASY, Flotow H, Fu NY, Butler MS, Soejarto DD, Buss AD, Yu VC (2003) Identification of chelerythrine as an inhibitor of Bcl-XL function. J Biol Chem 278:20453–20456
Enyedy IJ, Ling Y, Nacro K, Tomita Y, Wu X, Cao Y, Guo R, Li B, Zhu X, Huang Y, Long YQ, Roller PP, Yang D, Wang S (2001) Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening. J Med Chem 44:4313–4324
Wang JL, Liu D, Zhang ZJ, Shan S, Han X, Srinivasa SM, Croce C, Alnemri ES, Huang Z (2000) Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells. Proc Natl Acad Sci U S A 97:7124–7129
Leone M, Zhai D, Sareth S, Kitada S, Reed JC, Pellecchia M (2003) Cancer prevention by tea polyphenols is linked to their direct inhibition of antiapoptotic Bcl-2 family proteins. Cancer Res 63:8118–8121
Degterev A, Lugovskoy A, Cardone M, Mulley B, Wagner G, Mitchison T, Yuan J (2001) Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-XL. Nat Cell Biol 3:173–182
Yin H, Hamilton AD (2004) Terephthalamide derivatives as mimetics of the helical region of Bak peptide target Bcl-XL protein. Bioorg Med Chem Lett 14:1375–1379
Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hadjuk P, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng SC, Nimmer PM, O’Connor JM, Oleksijew A, Petro AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumors. Nature 435:677–681
Liu Z, Sun C, Olejniczak ET, Meadows RP, Betz SF, Oost T, Herrmann J, Wu JC, Fesik SW (2000) Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain. Nature 408:1004–1008
Sun H, Nikolovska-Coleska Z, Yang CY, Xu L, Liu M, Tomita Y, Pan H, Yoshioka Y, Krajewski K, Roller PP, Wang S (2004) Structure-based design of potent, conformationally constrained Smac mimetics. J Am Chem Soc 126:16686–16687
Oost TK, Sun C, Armstrong RC, Al-Assaad A-S, Betz SF, Deckwerth TL, Ding H, Elmore SW, Meadows RP, Olejniczak ET, Oleksijew A, Oltersdorf T, Rosenberg SH, Shoemaker AR, Tomaselli KJ, Zou H, Fesik SW (2004) Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer. J Med Chem 47:4417–4426
Chene P (2003) Inhibiting the p53–MDM2 interaction: an important target for cancer therapy. Nat Rev Cancer 3:102–109
Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, Pavletich N (1996) Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 274:948–953
Fry DC, Graves BJ, Vassilev LT (in press) Exploiting protein–protein interactions to design an activator of p53. In: Protein–protein interactions: a molecular cloning manual. Cold Spring Harbor Laboratory, New York
Fry DC, Graves B, Vassilev LT (in press) Development of E3–substrate (MDM2–p53) binding inhibitors: structural aspects. Methods Enzymol
Fry DC, Emerson SD, Palme S, Vu BT, Liu C-M, Podlaski F (2004) NMR structure of a complex between MDM2 and a small molecule inhibitor. J Biomol NMR 30:163–173
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Fry, D.C., Vassilev, L.T. Targeting protein–protein interactions for cancer therapy. J Mol Med 83, 955–963 (2005). https://doi.org/10.1007/s00109-005-0705-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00109-005-0705-x