Inhibitors of Cdc25 phosphatases as anticancer agents: A patent review

Expert Opinion on Therapeutic Patents

Volumn 20, Issue 3, 2010, Pages 405-425

  Lavecchia, Antonio ^a   Di Giovanni, Carmen ^a   Novellino, Ettore ^a  

^a UNIVERSITY OF NAPLES FEDERICO II   (Italy)

Author keywords

Antiproliferative agents; Cancer; Cdc25; Cdc25 inhibitors; Cell cycle; Dual specificity phosphatase; Protein tyrosine phosphatase

Indexed keywords

ANTINEOPLASTIC AGENT; BN 82685; CHOLESTANE DERIVATIVE; COSCINOSULPHATE; DYSIDIOLIDE; EP 0959884; EP 1226237; EP 1722781; EP 1831209; EP 1861395; IRC 083864; JP 2003104964; JP 2003508049; JP 2006316001; JP 2008524175; JP 2008532999; MALEIMIDE DERIVATIVE; OKADAIC ACID; PM 20; PROTEIN TYROSINE PHOSPHATASE; PROTEIN TYROSINE PHOSPHATASE INHIBITOR; SULFIRICIN; TBTPA 29; TPY 835; UNCLASSIFIED DRUG; UNINDEXED DRUG; US 20040097566; US 2006040996; US 20070244186; US 20070293487; US 2008039518; US 2008275094; US 20090131428; US 2009042872; US 2009082345; US 5700821; US 6011058; US 6949682; US 7279467; US 7495021; US 7504430; WO 0116300; WO 2005081972; WO 2006051202; WO 2006067311; WO 200610130; WO 2007081091; WO 20088149311; WO 9804257;

ADULT; ANTINEOPLASTIC ACTIVITY; BREAST CARCINOMA; CANCER CELL; CATALYSIS; CELL CYCLE REGULATION; CELL PROLIFERATION; CHEMICAL STRUCTURE; CYTOTOXICITY; DRUG DESIGN; DRUG EFFICACY; ENZYME INHIBITION; GENE EXPRESSION; GENE OVEREXPRESSION; HUMAN; IN VITRO STUDY; IN VIVO STUDY; MITOGENESIS; MOLECULE; NEOPLASM; NONHUMAN; PATENT; PROTEIN DEPHOSPHORYLATION; PROTEIN PHOSPHORYLATION; REVIEW; STRUCTURE ACTIVITY RELATION; TUMOR GROWTH; TUMOR VOLUME; TUMOR XENOGRAFT;

ANIMALS; ANTINEOPLASTIC AGENTS; CDC25 PHOSPHATASES; DRUG DESIGN; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; NEOPLASMS; PATENTS AS TOPIC; PROTEIN ISOFORMS; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 77649085550     PISSN: 13543776     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543771003623232     Document Type: Review

References (118)

1. Hunter T. Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signalling. Cell 1995;80:225-236
2. Denu JM, Stuckey MA, Saper M, Dixon JE. Form and function in protein dephosphorylation. Cell 1996;87:361-364
3. Fauman EB, Yuvaniyama C, Schubert HL, et al. The X-ray crystal structures of Yersinia tyrosine phosphatase with bound tungstate and nitrate. Mechanistic implications. J Biol Chem 1996;271:18780-18788
4. Barford D. Molecular mechanisms of the protein serine/threonine phosphatases. Trends Biochem Sci 1996;21:407-412
5. Alonso A, Sasin J, Bottini N, et al. Protein tyrosine phosphatases in the human genome. Cell 2004;117:699-711 (Pubitemid 38748887)
6. Arantes GM. Free-energy profiles for catalysis by dual-specificity phosphatases. J Biochem 2006;399:343-350
7. Arantes GM. The Catalytic Acid in the Dephosphorylation of the Cdk2-pTpY/ CycA Protein Complex by Cdc25B Phosphatase. J Phys Chem B 2008;112:15244-15247
8. Parks JM, Hu H, Rudolph J, Yang W. Mechanism of Cdc25B Phosphatase with the Small Molecule Substrate p-Nitrophenyl Phosphate from QM/MM-MFEP Calculations. J Phys Chem B 2009;113:5217-5224
9. Sadhu K, Reed SI, Richardson H, Russell P. Human homolog of fission yeast cdc25 mitotic inducer is predominantly expressed in G2. Proc Natl Acad Sci USA 1990;87:5139-5143
10. Nagata A, Igarashi M, Jinno S, et al. An additional homolog of the fission yeast cdc25+ gene occurs in humans and is highly expressed in some cancer cells. New Biol 1991;3:959-968
11. Galaktionov K, Beach D. Specific activation of cdc25 tyrosine phosphatases by B-type cyclins: evidence for multiple roles of mitotic cyclins. Cell 1991;167:1181-1194
12. Kristjansdottir K, Rudolph J. Cdc25 phosphatases and cancer. Chem Biol 2004;11:1043-1051
13. Galaktionov K, Lee AK, Eckstein J, et al. CDC25 phosphatases as potential human oncogenes. Science 1995;269:1575-1577
14. Cangi MG, Cukor B, Soung P, et al. Role of the Cdc25A phosphatase in human breast cancer. J Clin Invest 2000;106:753-761
15. Dixon D, Moyana T, King MJ. Elevated expression of the Cdc25A protein phosphatase in colon cancer. Exp Cell Res 1998;2:236-243
16. Gasparotto D, Maestro R, Piccinin S, et al. Overexpression of CDC25A and CDC25B in head and neck cancers. Cancer Res 1997;57:2366-2368
17. Hernández S, Hernández L, Bea S, et al. Cdc25a and the splicing variant cdc25b2, but not cdc25B1, -B3 or -C, are over-expressed in aggressive human non-Hodgkin's lymphomas. Int J Cancer 2000;89:148-152
18. Hu YC, Lam KY, Law S, et al. Profiling of differentially expressed cancer-related genes in esophageal squamous cell carcinoma (ESCC) using human cancer cDNA arrays: overexpression of oncogene MET correlates with tumor differentiation in ESCC. Clin Cancer Res 2001;7:3519-3525
19. Kudo Y, Yasui W, Ue T, et al. Overexpression of cyclin-dependent kinase-activating CDC25B phosphatase in human gastric carcinomas. Jpn J Cancer Res 1997;88:947-952
20. Sato Y, Sasaki H, Kondo S, et al. Expression of the Cdc25B mRNA correlated with that of N-myc in neuroblastoma. Jpn J Clin Oncol 2001;31:428-431 (Pubitemid 33039750)
21. Wu W, Fan YH, Kemp BL, et al. Overexpression of Cdc25A and Cdc25B is frequent in primary non-small cell lung cancer but is not associated with overexpression of c-myc. Cancer Res 1998;58:4082-4085
22. Galaktionov K, Chen X, Beach D. Cdc25 cell cycle phosphatase as a target of c-myc. Nature 1996;382:511-517
23. Ray D, Terao Y, Fuhrken PG, et al. Deregulated CDC25A expression promotes mammary tumorigenesis with genomic instability. Cancer Res 2007;67:984-991
24. Yao Y, Slosberg ED, Wang L, et al. Increased susceptibility to carcinogen induced mammary tumors in MMTV- Cdc25B transgenic mice. Oncogene 1999;18:5159-5166
25. Ozen M, Ittmann M. Increased expression and activity of CDC25C phosphatase and an alternatively spliced variant in prostate cancer. Clin Cancer Res 2005;11:4701-4706
26. Nurse P. A long twentieth century of the cell cycle and beyond. Cell 2000;100:71-78
27. Gautier J, Solomon MJ, Booher, et al. Cdc25 is a specific tyrosine phosphatase that directly activates p34Cdc2. Cell 1991;67:197-211
28. Kumagai A, Dunphy WG. The Cdc25 protein controls tyrosine dephosphorylation of the Cdc2 protein in a cell-free system. Cell 1991;64:903-914
29. Strausfeld U, Labbé JC, Fesquet D, et al. Dephosphorylation and activation of a p34Cdc2/cyclin B complex in vitro by human CDC25 protein. Nature 1991;35:242-245
30. Molinari M, Mercurio C, Dominguez J, et al. Human Cdc25 A inactivation in response to S phase inhibition and its role in preventing premature mitosis. EMBO Rep 2000;1:71-79
31. Karlsson-Rosenthal C, Katich S, Hagting A, et al. Cdc25B and Cdc25C differ markedly in their properties as initiators of mitosis. J Cell Biol 1999;146:573-584
32. De Souza CP, Ellem KA, Gabrielli BG. Centrosomal and cytoplasmic Cdc2/cyclin B1 activation precedes nuclear mitotic events. Exp Cell Res 2000;257:11-21
33. Hoffmann I, Clarke PR, Marcote MJ, et al. Phosphorylation and activation of human cdc25-C by cdc2-cyclin B and its involvement in the self-amplification of MPF at mitosis. EMBO J 1993;12:53-63
34. Izumi T, Maller, JL. Elimination of cdc2 phosphorylation sites in the cdc25 phosphatase blocks initiation of M-phase. Mol Biol Cell 1993;4:1337-1350
35. Strausfeld U, Fernandez A, Capony JP, et al. Activation of p34cdc2 protein kinase by microinjection of human cdc25C into mammalian cells. Requirement for prior phosphorylation of cdc25C by p34cdc2 on sites phosphorylated at mitosis. J Biol Chem 1994;269:5989-6000
36. Iliakis G, Wang Y, Guan J, Wang H. DNA damage checkpoint control in cells exposed to ionizing radiation. Oncogene 2003;22:5834-5847
37. Karlsson-Rosenthal C, Millar JB. Cdc25: mechanisms of checkpoint inhibition and recovery. Trends Cell Biol 2006;16:285-292
38. Keyse SM, Ginsburg M. Amino acid sequence similarity between CL100, a dual-specificity MAP kinase phosphatase and cdc25. Trends Biochem Sci 1993;18:377-378
39. Rudolph J. Targeting the Neighbor's Pool. Mol Pharmacol 2004;66:780-782
40. Rudolph J. Cdc25 phosphatases: structure, specificity and mechanism. Biochemistry 2007;46:3595-3604
41. Jackson MD, Denu JM. Molecular reactions of protein phosphatases-insights from structure and chemistry. Chem Rev 2001;101:2313-2340
42. Fauman EB, Cogswell JP, Lovejoy B, et al. Crystal structure of the catalytic domain of the human cell cycle control phosphatase, Cdc25A. Cell 1998;93:617-625
43. Reynolds RA, Yem AW, Wolfe CL, et al. Crystal structure of the catalytic subunit of Cdc25B required for G2/M phase transition of the cell cycle. J Mol Biol 1999;293:559-568
44. McCain DF, Catrina IE, Hengge AC, Zhang ZY. The catalytic mechanism of Cdc25A phosphatase. J Biol Chem 2002;277:11190-11200
45. Chen W, Wilborn M, Rudolph J. Dual-specific Cdc25B phosphatase: in search of the catalytic acid. Biochemistry 2000;39:10781-10789
46. Rudolph J. Catalytic mechanism of Cdc25. Biochemistry 2002;41:14613-14623
47. González-Ruiz D, Gohlke H. Targeting protein-protein interactions with small molecules: challenges and perspectives for computational binding epitope detection and ligand finding. Curr Med Chem 2006;13:2607-2625
48. Wells JA, McClendon CL. Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 2007;450:1001-1009
49. Sohn J, Kristjansdottir K, Safi A, et al. Remote hot spots mediate protein substrate recognition for the Cdc25 phosphatase. Proc Natl Acad Sci USA 2004;101:16437-16441
50. Sohn J, Parks JM, Buhrman G, et al. Experimental validation of the docking orientation of Cdc25 with its Cdk2-CycA protein substrate. Biochemistry 2005;44:16563-16573
51. Horiguchi T, Nishi K, Hakoda S, et al. Dnacin A1 and dnacin B1 are antitumor antibiotics that inhibit cdc25B phosphatase activity. Biochem Pharmacol 1994;48:2139-2141
52. Gunasekera SP, McCarthy PJ, Kelly-Borges M, et al. Dysidiolide: A Novel Protein Phosphatase Inhibitor from the Caribbean Sponge Dysidea etheria de Laubenfels. J Am Chem Soc 1996;118:8759-8760
53. Lavecchia A, Di Giovanni C, Novellino E. Cdc25A and B dual-specifity phosphatase inhibitors: potential agents for cancer therapy. Curr Med Chem 2009;16:1831-1849
54. Lavecchia A, Coluccia A, Di Giovanni C, Novellino E. Cdc25B phosphatase inhibitors in cancer therapy: latest developments, trends and medicinal chemistry perspective. Anticancer Agents Med Chem 2008;8:843-856
55. Contour-Galcera MO, Sidhu A, Prévost G, et al. What's new on CDC25 phosphatase inhibitors. Pharmacol Ther 2007;115:1-12
56. Garuti L, Roberti M, Pizzirani D. Synthetic small molecule Cdc25 phosphatases inhibitors. Curr Med Chem 2008;15:573-580
57. Georgia Tech Research Corp. Seco-cholestane derivatives and methods of making the same. US6011058; 2000
58. Peng H, Zalkow LH, Abraham RT, et al. Cdc25A phosphatase inhibitors from pyrolysis of 3-alpha-azido-B-homo- 6-oxa-4-cholesten-7-one on silica gel. J Med Chem 1998;41:4677-4680
59. Lyon MA, Ducruet AP, Wipf P, Lazo JS. Dual-specificity phosphatases as targets for antineoplastic agents. Nature Rev Drug Discov 2002;1:961-976
60. Umezawa K, Kawakami M, Watanabe T. Molecular design and biological activities of protein-tyrosine phosphatase inhibitors. Pharmacol Ther 2003;99:15-24
61. Miyaoka H, Kajiwara Y, Hara Y, Yamada Y. Total synthesis of natural dysidiolide. J Org Chem 2001;66:1429-1435
62. Dodo K, Takahashi M, Yamada Y, et al. Synthesis of a novel class of cdc25A inhibitors from vitamin D3. Bioorg Med Chem Lett 2000;10:615-617
63. Takahashi M, Dodo K, Sugimoto Y, et al. Synthesis of the novel analogues of dysidiolide and their structure-activity relationship. Bioorg Med Chem Lett 2000;10:2571-2574
64. Peng H, Xie W, Otterness DM, et al. Syntheses and biological activities of a novel group of steroidal derived inhibitors for human Cdc25A protein phosphatase. J Med Chem 2001;44:834-848
65. Brohm D, Metzger S, Bhargava A, et al. Natural products are biologically validated starting points in structural space for compound library development: solid-phase synthesis of dysidiolide-derived phosphatase inhibitors. Angew Chem Int 2002;41:307-311
66. Brohm D, Philippe N, Metzger S, et al. Solid-phase synthesis of dysidiolide-derived protein phosphatase inhibitors. J Am Chem Soc 2002;124:13171-13178
67. Poigny S, Nouri S, Chiaroni A, et al. Total synthesis and determination of the absolute configuration of coscinosulfate, a new selective inhibitor of Cdc25 protein phosphatase. J Org Chem 2001;66:7263-7269
68. Wright AE, McCarthy PJ, Schulte GK. Sulfircin e a new sesterterpene sulfate from a deep-water sponge of the genus Ircinia. J Org Chem 1989;54:3472-3474
69. Cebula RE, Blanchard JL, Boissclair MD, et al. Synthesis and phosphatase inhibitory activity of analogs of sulfircin. Bioorg Med Chem Lett 1997;7:2015-2020
70. University of Pittsburgh. Phosphatase inhibitors and methods of use thereof. US5700821; 1997
71. University of Pittsburgh. Phosphatase inhibitors and methods of use thereof. EP0959884; 1999
72. University of Pittsburgh. Phosphatase inhibitors and methods of use thereof. WO9804257; 1998
73. Rice RL, Rusnak JM, Yokokawa F. A targeted library of small-molecule, tyrosine, and dual-specificity phosphatase inhibitors derived from a rational core design and random side chain variation. Biochemistry 1997;36:15965-15974
74. Ducruet AP, Rice RL, Tamura K, et al. Identification of new Cdc25 dual specificity phosphatase inhibitors in a targeted small molecule array. Bioorg Med Chem 2000;8:1451-1466
75. Wipf P, Cunningham A, Rice RL, Lazo JS. Small-molecule Ser/Thr-protein phosphatase inhibitors. Bioorg Med Chem 1997;5:165-177
76. Basf AG. Method of identifying inhibitors of cdc25. WO0116300; 2001
77. Basf AG; GPC Biotech Inc. Method of identifying inhibitors of cdc25. EP1226237; 2002
78. Basf AG. Method of identifying inhibitors of cdc25. JP2003508049; 2003
79. Taiho Pharmaceutical Co Ltd New carboxylic acid derivative having activity for inhibiting cdc25 dephosphorylation enzyme, and medicine. JP2003104964; 2003
80. Aoyagi Y, Masuko N, Ohkubo S, et al. A novel cinnamic acid derivative that inhibits Cdc25 dual-specificity phosphatase activity. Cancer Sci 2005;96:614-619
81. Korea Research Institute of Bioscience and Biotechnology. Cinnamaldehyde derivatives inhibiting growth of tumor cell and regulating cell cycle, preparations and pharmaceutical compositions thereof. US6949682; 2004
82. Shin DS, Kim JH, Lee SK, et al. Synthesis and biological evaluation of dimeric cinnamaldehydes as potent antitumor agents. Bioorg Med Chem 2006;14:2498-2506
83. Korea Research Institute of Chemical Technology. 5-(1,3-diaryl-1h- pyrazol- 4-ylmethylene)-thiazolidine-2,4-dione derivatives useful as anticancer agent. WO2006101307; 2006
84. Korea Research Institute of Chemical Technology. 5-(1,3-diaryl-1h- pyrazol- 4-ylmethylene)-thiazolidine-2,4-dione derivatives useful as anticancer agent. US2008275094; 2008
85. Korea Research Institute of Chemical Technology. 5-(1,3-diaryl-1h- pyrazol- 4-ylmethylene)-thiazolidine-2,4-dione derivatives useful as anticancer agent. EP1861395; 2007
86. Korea Research Institute of Chemical Technology. 5-(1,3-diaryl-1h- pyrazol- 4-ylmethylene)-thiazolidine-2,4-dione derivatives useful as anticancer agent. JP2008532999; 2008
87. Korea Research Institute of Bioscience and Biotechnology; Korea Research Institute of Chemical Technology. Rhodanine derivarives, a process for the preparation thereof and pharmaceutical composition containing the same. WO2007081091; 2007
88. Korea Research Institute of Bioscience and Biotechnology; Korea Research Institute of Chemical Technology. Rhodanine derivarives, a process for the preparation thereof and pharmaceutical composition containing the same. US2009042872; 2009
89. Pfhal M, Al-Shamma H, Giachino AF, et al. 2-Substituted thiazolidinone and oxazolidinone derivatives for the inhibition of phosphatases and the treatment of cancer. US20040097566; 2004
90. Bao H, Fanjul A, Al-Shamma H, et al. A novel class of Cdc25 phosphatase inhibitors shows potent anticancer activity by blocking cell cycle and inducing apoptosis. Eur J Cancer 2002;38:50-51
91. Kar S, Wang M, Yao W, et al. PM-20, a novel inhibitor of Cdc25A, induces extracellular signal-regulated kinase 1/2 phosphorylation and inhibits hepatocellular carcinoma growth in vitro and in vivo. Mol Cancer Ther 2006;5:1511-1519
92. US Government, Department of Health and Human Services. Maleiimide anti-tumor phosphatase inhibitors. US2008039518; 2008
93. US Government, Department of Health and Human Services. Maleiimide anti-tumor phosphatase inhibitors. US7504430; 2009
94. US Government, Department of Health and Human Services. Maleiimide anti-tumor phosphatase inhibitors. EP1722781; 2006
95. US Government; Department of Health and Human Services US. Maleiimide anti-tumor phosphatase inhibitors. WO2005081972; 2005
96. Keio University. Naphthoquinone derivative compound or pharmacologically allowable salt thereof, and Cdc25 phosphatase inhibitor and antitumor agent containing same as active ingredient. JP2006316001; 2006
97. Societe de Conseils de Recherches et d'Applications Scientifiques (S.C.R.A.S.). Benzothiazole-and benzooxazole-4, 7-dione derivatives and their use as Cdc25 phosphatase inhibitors. US7279467; 2007
98. Societe de Conseils de Recherches et d'Applications Scientifiques (S.C.R.A.S). Benzothiazole-and benzooxazole-4, 7-dione derivatives and their use as Cdc25 phosphatase inhibitors. US2006040996; 2006
99. Societe de Conseils de Recherches et d'Applications Scientifiques (S.C.R.A.S). Benzothiazole-and benzooxazole-4, 7-dione derivatives and their use as Cdc25 phosphatase inhibitors. US7495021; 2009
100. Societe de Conseils de Recherches et d'Applications Scientifiques (S.C.R.A.S). Benzothiazole-and benzooxazole-4, 7-dione derivatives and their use as Cdc25 phosphatase inhibitors. US20070293487; 2007
101. Societe de Conseils de Recherches et d'Applications Scientifiques (S.C.R.A.S). Benzothiazole-and benzooxazole-4, 7-dione derivatives and their use as Cdc25 phosphatase inhibitors. US2009082345; 2009
102. Societe de Conseils de Recherches et d'Applications Scientifiques (S.C.R.A.S). Benzooxazole-4, 7-dione derivatives and their use as Cdc25 phosphatase inhibitors. US20090131428; 2009
103. Societe de Conseils de Recherches et d'Applications Scientifiques (S.C.R.A.S). 4,7 Dioxobenzothiazole-2-Carboxamide Derivatives, Their Preparation and Their Therapeutic Uses. US20070244186; 2007
104. Societe de Conseils de Recherches et d'Applications Scientifiques (S.C.R.A.S). 4,7-Dioxobenzothiazole-2-Carboxamide Derivatives, Their Preparation and Their Therapeutic Uses. WO2006051202; 2006
105. Brezak MC, Quaranta M, Contour-Galcera MO, et al. Inhibition of human tumor cell growth in vivo by an orally bioavailable inhibitor of CDC25 phosphatases. Mol Cancer Ther 2005;4:1378-1387
106. Cazales M, Boutros R, Brezak MC, et al. Pharmacologic inhibition of CDC25 phosphatases impairs interphase microtubule dynamics and mitotic spindle assembly. Mol Cancer Ther 2007;6:318-325
107. Societe de Conseils de Recherches et d'Applications Scientifiques (S.C.R.A.S). CDC25 phosphatase inhibitors. WO2006067311; 2006
108. Societe de Conseils de Recherches et d'Applications Scientifiques (S.C.R.A.S). CDC25 phosphatase inhibitors. EP1831209; 2007
109. Societe de Conseils de Recherches et d'Applications Scientifiques (S.C.R.A.S). CDC25 phosphatase inhibitors. JP2008524175; 2008
110. Brezak MC, Valette A, Quaranta M, et al. IRC-083864, a novel bis quinone inhibitor of CDC25 phosphatases active against human cancer cells. A novel synthetic CDC25 phosphatase inhibitor inhibits human cancer cells. Int J Cancer 2009;124:1449-1456
111. Institut National de la Sante et de la Recherche Medicale (INSERM). Use of derivatives of 3-oxo-2,3-dihydro- 5H-thiazolof [3,2-A] pyrimidine or of 3-oxo-2,3-dihydro-5H-selenazolo[3,2-A] pyrimidine or of 3-oxo-1,2,3-trihydro-5H- imidazolo [1,2-A] pyrimidine for the preparation of pharmaceutical compositions intended for the treatment of cancer. WO2008149311; 2008
112. Montes M, Braud E, Miteva MA, et al. Receptor-based virtual ligand screening for the identification of novel CDC25 phosphatase inhibitors. J Chem Inf Model 2008;48:157-165
113. Duval R, Kolb S, Braud E, et al. Rapid Discovery of Triazolobenzylidene- Thiazolopyrimidines (TBTP) as CDC25 Phosphatase Inhibitors by Parallel Click Chemistry and in Situ Screening. J Comb Chem 2009;11:947-950
114. Lavecchia A, Cosconati S, Limongelli V, Novellino E. Modeling of Cdc25B dual specifity protein phosphatase inhibitors: docking of ligands and enzymatic inhibition mechanism. Chem Med Chem 2006;1:540-550
115. Sherman W, Day T, Jacobson MP, et al. Novel procedure for modeling ligand/receptor induced fit effects. J Med Chem 2006;49:534-553
116. Knight JL, Zhou ZY, Gallicchio E, et al. Exploring structural variability in X-ray crystallographic models using protein local optimization by torsion-anglesampling. Acta Crystallogr D Biol Crystallogr 2008;64:383-396
117. Van Duyne GD, Standaert RF, Karplus PA, et al. Atomic structures of the human immunophilin FKBP-12 complexes with FK506 and rapamycin. J Mol Biol 1993;229:105-124
118. Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004;303:844-848