Cited by 134Chemical Synthesis and AnalysisCancer-related Molecular PathwaysProtein Structure and Dynamics

Structure–Activity Studies in a Family of β‐Hairpin Protein Epitope Mimetic Inhibitors of the p53–HDM2 Protein–Protein Interaction

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Fasan, Rudi, Dias, Ricardo L. A., Moehle, Kerstin, Zerbe, Oliver, Obrecht, Daniel, Mittl, Peer R. E., Grütter, Markus G., Robinson, John A.·2006·ChemBioChem

Abstract

Inhibitors of the interaction between the p53 tumor‐suppressor protein and its natural human inhibitor HDM2 are attractive as potential anticancer agents. In earlier work we explored designing β‐hairpin peptidomimetics of the α‐helical epitope on p53 that would bind tightly to the p53‐binding site on HDM2. The β‐hairpin is used as a scaffold to display energetically hot residues in an optimal array for interaction with HDM2. The initial lead β‐hairpin mimetic, with a weak inhibitory activity (IC 50=125 μM), was optimized to afford cyclo‐(L‐Pro‐Phe‐Glu‐6ClTrp‐Leu‐Asp‐Trp‐Glu‐Phe‐D‐Pro) (where 6ClTrp=L‐6‐chlorotryptophan), which has an affinity almost 1000 times higher (IC 50=140 n M). In this work, insights into the origins of this affinity maturation based on structure–activity studies and an X‐ray crystal structure of the inhibitor/HDM2(residues 17–125) complex at 1.4 Å resolution are described. The crystal structure confirms the β‐hairpin conformation of the bound ligand, and also reveals that a significant component of the affinity increase arises through new aromatic/aromatic stacking interactions between side chains around the hairpin and groups on the surface of HDM2.

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  1. D. Reichmann, O. Rahat, S. Albeck, R. Meged, O. Dym, G. Schreiber, Proc. Natl. Acad. Sci. USA 2005, 102, 57.
  2. A. A. Bogan, K. S. Thorn, J. Mol. Biol. 1998, 280, 1.
  3. T. Clackson, J. A. Wells, Science 1995, 267, 383.
  4. T. Clackson, M. H. Ultsch, J. A. Wells, A. M. de Vos, J. Mol. Biol. 1998, 277, 1111.
  5. L. Lo Conte, C. Chothia, J. Janin, J. Mol. Biol. 1999, 285, 2177.
  6. P. L. Toogood, J. Med. Chem. 2002, 45, 1543.
  7. J. A. Wells, Proc. Natl. Acad. Sci. USA 1996, 93, 1.
  8. J. Späth, F. Stuart, L. Jiang, J. A. Robinson, Helv. Chim. Acta 1998, 81, 1726.
  9. L. Jiang, K. Moehle, B. Dhanapal, D. Obrecht, J. A. Robinson, Helv. Chim. Acta 2000, 83, 3097.
  10. M. Favre, K. Moehle, L. Jiang, B. Pfeiffer, J. A. Robinson, J. Am. Chem. Soc. 1999, 121, 2679.
  11. A. Descours, K. Moehle, A. Renard, J. A. Robinson, ChemBioChem 2002, 3, 318.
  12. J. A. Robinson, S. C. Shankaramma, P. Jetter, U. Kienzl, R. A. Schwenden- er, J. W. Vrijbloed, D. Obrecht, Bioorg. Med. Chem. 2005, 13, 2055.
  13. S. C. Shankaramma, Z. Athanassiou, O. Zerbe, K. Moehle, C. Mouton, F. Bernardini, J. W. Vrijbloed, D. Obrecht, J. A. Robinson, ChemBioChem 2002, 3, 1126.
  14. Z. Athanassiou, R. L. A. Dias, K. Moehle, N. Dobson, G. Varani, J. A. Robinson, J. Am. Chem. Soc. 2004, 126, 6906.
  15. R. Fasan, R. L. A. Dias, K. Moehle, O. Zerbe, J. W. Vrijbloed, D. Obrecht, J. A. Robinson, Angew. Chem. 2004, 116, 2161; Angew. Chem. Int. Ed. 2004, 43, 2109.
  16. P. ChØne, Nat. Rev. Cancer 2003, 3, 102.
  17. P. H. Kussie, S. Gorina, V. Marechal, B. Elenbaas, J. Moreau, A. J. Levine, N. P. Pavletich, Science 1996, 274, 948.
  18. O. Schon, A. Friedler, M. Bycroft, S. M. Freund, A. R. Fersht, J. Mol. Biol. 2002, 323, 491.
  19. Z. Lai, K. R. Auger, C. M. Manubay, R. A. Copeland, Arch. Biochem. Bio- phys. 2000, 381, 278.
  20. B. L. Sibanda, J. M. Thornton, Methods Enzymol. 1991, 202, 59.
  21. B. Meyer, T. Peters, Angew. Chem. 2003, 115, 890; Angew. Chem. Int. Ed. 2003, 42, 864.
  22. S. W. Homans, Angew. Chem. 2004, 116, 292; Angew. Chem. Int. Ed. 2004, 43, 290.
  23. P. J. Hajduk, R. P. Meadows, S. W. Fesik, Quart. Rev. Biophys. 1999, 32, 211.
  24. R. Stoll, C. Renner, P. Mühlhahn, S. Hansen, R. Schumacher, F. Hesse, B. Kaluza, R. A. Engh, W. Voelter, T. A. Holak, J. Biomol. NMR 2000, 17, 91.
  25. O. Schon, A. Friedler, S. Freund, A. R. Fersht, J. Mol. Biol. 2004, 336, 197.
  26. S. H. Gellman, Curr. Opin. Chem. Biol. 1998, 2, 717.
  27. M. S. Searle, J. Chem. Soc. Perkin Trans. 2 2001, 1011.
  28. M. S. Searle, B. Ciani, Curr. Opin. Struct. Biol. 2004, 14, 458.
  29. M. Rainaldi, V. Moretto, M. Crisma, E. Peggion, S. Mammi, C. Toniolo, G. Cavicchioni, J. Pept. Sci. 2002, 8, 241.
  30. Y. Takeuchi, G. R. Marshall, J. Am. Chem. Soc. 1998, 120, 5363.
  31. C. Garcia-Echeverria, P. ChØne, M. J. J. Blommers, P. Furet, J. Med. Chem. 2000, 43, 3205.
  32. M. C. Lawrence, P. M. Colman, J. Mol. Biol. 1993, 234, 946.
  33. L. T. Vassilev, B. T. Vu, B. Graves, D. Carvajal, F. Podlaski, Z. Filipovic, N. Kong, U. Kammlott, C. Lukacs, C. Klein, N. Fotouhi, E. A. Liu, Science 2004, 303, 844.
  34. S. Uhrinova, D. Uhrin, H. Powers, K. Watt, D. Zheleva, P. Fischer, C. McInnes, P. N. Barlow, J. Mol. Biol. 2005, 350, 587.
  35. S. K. Burley, G. A. Petsko, Science 1985, 229, 23.
  36. C. A. Hunter, J. Singh, J. M. Thornton, J. Mol. Biol. 1991, 218, 837.
  37. E. A. Meyer, R. K. Castellano, F. Diederich, Angew. Chem. 2003, 115, 1244; Angew. Chem. Int. Ed. 2003, 42, 1210.
  38. M. A. McCoy, J. J. Gesell, M. M. Senior, D. F. Wyss, Proc. Natl. Acad. Sci. USA 2003, 100, 1645.
  39. H. Adams, S. Cockroft, C. Guardigli, C. A. Hunter, K. R. Lawson, J. Perkins, S. E. Spey, C. J. Urch, R. Ford, ChemBioChem 2004, 5, 657.
  40. D. A. Dougherty, Science 1996, 271, 163.
  41. S. K. Burley, G. A. Petsko, FEBS Lett. 1986, 203, 139.
  42. M. T. Stubbs, S. Reyda, F. Dullweber, M. Müller, G. Klebe, D. Dorsch, W. W. K. R. Mederski, H. Wurziger, ChemBioChem 2002, 3, 246.
  43. S. Maignan, J.-P. Guilloteau, Y. M. Choi-Sledeski, M. R. Becker, W. R. Ewing, H. W. Pauls, A. P. Spada, V. Mikol, J. Med. Chem. 2003, 46, 685.
  44. N. Haginoya, S. Kobayashi, S. Komoriya, T. Yoshino, M. Suzuki, T. Shi- mada, K. Watanabe, Y. Hirokawa, T. Furugori, T. Nagahara, J. Med. Chem. 2004, 47, 5167.
  45. M. Adler, M. J. Kochanny, B. Ye, G. Rumennik, D. R. Light, S. Biancalana, M. Whitlow, Biochemistry 2002, 41, 15 514.
  46. T. J. Tucker, S. F. Brady, W. C. Lumma, S. D. Lewis, S. J. Gardel, A. M. Naylor-Olsen, Y. Yan, J. T. Sisko, K. J. Stauffer, B. Y. Lucas, J. J. Lynch, J. J. Cook, M. T. Stranieri, M. A. Holahan, E. A. Lyle, E. P. Baskin, I.-W. Chen, K. B. Dancheck, J. A. Krueger, C. M. Cooper, J. P. Vacca, J. Med. Chem. 1998, 41, 3210.
  47. G. Gerebtzoff, X. LiBlatter, H. Fischer, A. Frentzel, A. Seelig, ChemBio- Chem 2004, 5, 676.
  48. S. J. Duncan, S. Grüschow, D. H. Williams, C. McNicholas, R. Purewal, M. Hajek, M. Gerlitz, S. Martin, S. K. Wrigley, M. Moore, J. Am. Chem. Soc. 2001, 123, 554.
  49. V. J. Huber, T. W. Arroll, C. Lum, B. A. Goodman, H. Nakanishi, Tetrahe- dron Lett. 2002, 43, 6729.
  50. S. M. G. Knight, N. Umezawa, H.-S. Lee, S. H. Gellman, B. K. Kay, Anal. Bio- chem. 2002, 300, 230.
  51. M. Kanovsky, A. Raffo, L. Drew, R. Rosal, T. Do, F. K. Friedman, P. Rubin- stein, J. Visser, R. Robinson, P. W. Brandt-Rauf, J. Michl, R. L. Fine, M. R. Pincus, Proc. Natl. Acad. Sci. USA 2001, 98, 12 438.
  52. A. Bçttger, V. Bçttger, A. Sparks, W.-L. Liu, S. F. Howard, D. P. Lane, Cur- rent Biol. 1997, 7, 860.
  53. V. Bçttger, A. Bçttger, S. F. Howard, S. M. Picksley, P. ChØne, C. Garcia- Echeverria, H.-K. Hochkeppel, D. P. Lane, Oncogene 1996, 13, 2141.
  54. P. ChØne, J. Fuchs, J. Bohn, C. Garcia-Echeverria, P. Furet, D. Fabbro, J. Mol. Biol. 2000, 299, 245.
  55. C. Garcia-Echeverria, P. Furet, P. ChØne, Bioorg. Med. Chem. Lett. 2001, 11, 2161.
  56. R. Banerjee, G. Basu, P. ChØne, S. Roy, J. Pept. Res. 2002, 60, 88.
  57. B. L. Grasberger, T. B. Lu, C. Schubert, D. J. Parks, T. E. Carver, H. K. Kob- lish, M. D. Cummings, L. V. LaFrance, K. L. Milkiewicz, R. R. Calvo, D. Ma- guire, J. Lattanze, C. F. Franks, S. Y. Zhao, K. Ramachandren, G. R. Bylebyl, M. Zhang, C. L. Manthey, E. C. Petrella, M. W. Pantoliano, I. C. Deckman, J. C. Spurlino, A. C. Maroney, B. E. Tomczuk, C. J. Molloy, R. F. Bone, J. Med. Chem. 2005, 48, 909.
  58. J. A. Kritzer, J. D. Lear, M. E. Hodsdon, A. Schepartz, J. Am. Chem. Soc. 2004, 126, 9468.
  59. J. A. Kritzer, M. E. Hodsdon, A. Schepartz, J. Am. Chem. Soc. 2005, 127, 4118.
  60. M. M. Reddy, K. Bachhawat-Sikder, T. Kodadek, Chem. Biol. 2004, 11, 1127.
  61. R. Stoll, C. Renner, S. Hansen, S. Palme, C. Klein, A. Belling, W. Zeslawski, M. Kamionka, T. Rehm, P. Muhlhahn, R. Schumacher, F. Hesse, B. Kaluza, W. Voelter, R. A. Engh, T. A. Holak, Biochemistry 2001, 40, 336.
  62. I. R. Hardcastle, S. U. Ahmed, H. Atkins, A. H. Calvert, N. J. Curtin, G. Farnie, B. T. Golding, R. J. Griffin, S. Guyenne, C. Hutton, P. Kallbad, S. J. Kemp, M. S. Kitching, D. R. Newell, S. Norbedo, J. S. Northen, R. J. Reid, K. Saravanan, H. M. G. Willems, J. Lunec, Bioorg. Med. Chem. Lett. 2005, 15, 1515.
  63. D. J. Parks, L. V. LaFrance, R. R. Calvo, K. L. Milkiewicz, V. Gupta, J. Lat- tanze, K. Ramachandren, T. E. Carver, E. C. Petrella, M. D. Cummings, D. Maguire, B. L. Grasberger, T. B. Lu, Bioorg. Med. Chem. Lett. 2005, 15, 765.
  64. H. Yin, G. I. Lee, H. S. Park, G. A. Payne, J. M. Rodriguez, S. M. Sebti, A. D. Hamilton, Angew. Chem. 2005, 117, 2764; Angew. Chem. Int. Ed. 2005, 44, 2704.
  65. L. H. Chen, H. Yin, B. Farooqi, S. Sebti, A. D. Hamilton, J. D. Chen, Mol. Cancer Ther. 2005, 4, 1019.
  66. P. S. Galatin, D. J. Abraham, J. Med. Chem. 2004, 47, 4163.
  67. W. Kabsch, J. Appl. Crystallogr. 1988, 21, 916.
  68. J. Navaza, E. H. Panepucci, C. Martin, Acta Crystallogr. Sect. D Biol. Crys- tallogr. 1998, 54, 817.
  69. G. N. Murshudov, A. A. Vagin, A. Lebedev, K. S. Wilson, E. J. Dodson, Acta Crystallogr. Sect. D Biol. Crystallogr. 1999, 55, 247.
  70. G. M. Sheldrick, T. R. Schneider, Methods Enzymol. 1997, 277, 319.
  71. A. Nicholls, K. Sharp, B. Honig, Proteins 1991, 11, 281.
  72. R. Koradi, M. Billeter, K. Wüthrich, J. Mol. Graphics 1996, 14, 51.
  73. R. M. Esnouf, J. Mol. Graphics Modell. 1997, 15, 132.
  74. P. Güntert, C. Mumenthaler, K. Wüthrich, J. Mol. Biol. 1997, 273, 283.
  75. C. Bartels, T. Xia, M, Billeter, P. Guentert, K. Wüthrich, J. Biomol. NMR 1995, 6, 1. Received: November 2, 2005 526 www.chembiochem.org 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemBioChem 2006, 7, 515 -526

Cited by

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Authors
Fasan, R., Dias, R. L. A., Moehle, K., Zerbe, O., Obrecht, D., Mittl, P. R. E., Grütter, M. G., & Robinson, J. A.
Affiliations
  • University of Zurich (CH)
  • Polyphor (Switzerland) (CH)
Venue
ChemBioChem
Publisher
Wiley
Published
2006-03
Volume
7
Issue
3
Pages
515-526
ISSN
  • 1439-4227 (ISSN-L)
  • 1439-7633
OpenAlex
W2003327089
Cited by
129
References
84
Citations by year
2026: 1 · 2025: 2 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 7 · 2019: 7 · 2018: 3 · 2017: 3 · 2016: 14 · 2015: 13 · 2014: 8 · 2013: 11 · 2012: 6
FWCI
3.81
Type
journal article
Language
en
Open access
Locations
  • ChemBioChem (publishedVersion)
  • PubMed (publishedVersion)
  • DORA PSI (Paul Scherrer Institute) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
p53-MDM2 interaction, protein-protein interaction inhibitors, structure-activity relationship, affinity maturation, π-π stacking, X-ray crystal structure, anticancer agents, p53 tumor suppressor
MeSH terms
Amino Acid Sequence, Epitopes, Crystallization, Models, Molecular, Protein Binding, Protein Conformation, Structure-Activity Relationship, Tumor Suppressor Protein p53, Molecular Mimicry, Nuclear Magnetic Resonance, Biomolecular, Proto-Oncogene Proteins c-mdm2

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