Targeting protein-protein interactions in hematologic malignancies: Still a challenge or a great opportunity for future therapies?

Immunological Reviews

Volumn 263, Issue 1, 2015, Pages 279-301

  Cierpicki, Tomasz ^a   Grembecka, Jolanta ^a  

^a UNIVERSITY OF MICHIGAN   (United States)

Author keywords

Drug discovery; Hematologic malignancies; Protein protein interactions

Indexed keywords

4 (4 CHLOROPHENYL) 2,3,9 TRIMETHYL 6H THIENO[3,2 F][1,2,4]TRIAZOLO[4,3 A][1,4]DIAZEPINE 6 ACETIC ACID TERT BUTYL ESTER; 4 (4 CHLOROPHENYL) N (4 HYDROXYPHENYL) 2,3,9 TRIMETHYL 6H THIENO[3,2 F][1,2,4]TRIAZOLO[4,3 A][1,4]DIAZEPINE 6 ACETAMIDE; 4 [4 (4' CHLORO 2 BIPHENYLYLMETHYL) 1 PIPERAZINYL] N [4 [3 DIMETHYLAMINO 1 (PHENYLTHIOMETHYL)PROPYLAMINO] 3 NITROBENZENESULFONYL]BENZAMIDE; 5 (4 CHLORO 3 NITROPHENYL) 1,4 DIPHENYL 1,2,4 TRIAZOLIUM 3 THIOLATE; 6 (4 CHLOROPHENYL) N ETHYL 8 METHOXY 1 METHYL 4H [1,2,4]TRIAZOLO[4,3 A][1,4]BENZODIAZEPINE 4 ACETAMIDE; BIRINAPANT; BROMODOMAIN INHIBITOR; CORE BINDING FACTOR BETA; ENZYME INHIBITOR; HYBRID PROTEIN; INTRINSICALLY DISORDERED PROTEIN; METHIONINE; MIXED LINEAGE KINASE; N [1 CYCLOHEXYL 2 [2 [4 (4 FLUOROBENZOYL) 2 THIAZOLYL] 1 PYRROLIDINYL] 2 OXOETHYL] 2 (METHYLAMINO)PROPANAMIDE; NATURAL PRODUCT; NAVITOCLAX; OBATOCLAX; PEPTIDE FRAGMENT; PEPTIDOMIMETIC AGENT; PROTEIN; SHORT HAIRPIN RNA; VEMURAFENIB; [2 (4 TERT BUTYL 2 ETHOXYPHENYL) 4,5 BIS(4 CHLOROPHENYL) 4,5 DIHYDRO 4,5 DIMETHYL 1H IMIDAZOL 1 YL][4 [3 (METHYLSULFONYL)PROPYL] 1 PIPERAZINYL]METHANONE; ANTINEOPLASTIC AGENT;

ACUTE LEUKEMIA; ACUTE MYELOBLASTIC LEUKEMIA; APOPTOSIS; ARTICLE; CANCER CHEMOTHERAPY; CANCER PATIENT; CANCER RESEARCH; CELL DIFFERENTIATION; CLINICAL TRIAL (TOPIC); COMPUTATIONAL FLUID DYNAMICS; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG INDUSTRY; DRUG TARGETING; HEMATOLOGIC MALIGNANCY; HEMATOLOGY; HIGH THROUGHPUT SCREENING; HUMAN; IC50; LEUKEMIA CELL LINE; MOLECULAR DYNAMICS; MOLECULAR WEIGHT; MOLECULE; NONHUMAN; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN BINDING; PROTEIN CONFORMATION; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; PROTEIN TARGETING; ANIMAL; BIOLOGY; DRUG DEVELOPMENT; GENETICS; HEMATOLOGIC NEOPLASMS; MOLECULARLY TARGETED THERAPY; PROTEIN DOMAIN;

ANIMALS; ANTINEOPLASTIC AGENTS; CLINICAL TRIALS AS TOPIC; COMPUTATIONAL BIOLOGY; DRUG DISCOVERY; HEMATOLOGIC NEOPLASMS; HUMANS; MOLECULAR TARGETED THERAPY; PROTEIN INTERACTION DOMAINS AND MOTIFS;

EID: 84930348435     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/imr.12244     Document Type: Article

References (200)

1. Moore AS, Kearns PR, Knapper S, Pearson AD, Zwaan CM. Novel therapies for children with acute myeloid leukaemia. Leukemia 2013;27:1451-1460.
2. Napper AD, Watson VG. Targeted drug discovery for pediatric leukemia. Front Oncol 2013;3:170.
3. Tasian SK, Pollard JA, Aplenc R. Molecular Therapeutic Approaches for Pediatric Acute Myeloid Leukemia. Front Oncol 2014;4:55.
4. Brown P, Hunger SP, Smith FO, Carroll WL, Reaman GH. Novel targeted drug therapies for the treatment of childhood acute leukemia. Expert Rev Hematol 2009;2:145.
5. Niewerth D, Dingjan I, Cloos J, Jansen G, Kaspers G. Proteasome inhibitors in acute leukemia. Expert Rev Anticancer Ther 2013;13:327-337.
6. Fandy TE. Development of DNA methyltransferase inhibitors for the treatment of neoplastic diseases. Curr Med Chem 2009;16:2075-2085.
7. Giannini G, Cabri W, Fattorusso C, Rodriquez M. Histone deacetylase inhibitors in the treatment of cancer: overview and perspectives. Future Med Chem 2012;4:1439-1460.
8. Daigle SR, et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 2011;20:53-65.
9. Figueroa ME, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010;18:553-567.
10. Rodriguez-Paredes M, Esteller M. Cancer epigenetics reaches mainstream oncology. Nat Med 2011;17:330-339.
11. Meldi KM, Figueroa ME. Epigenetic deregulation in myeloid malignancies. Transl Res 2014; pii:S1931-5244(14)00142-X.
12. Ofran Y, Rowe JM. Genetic profiling in acute myeloid leukaemia-where are we and what is its role in patient management. Br J Haematol 2013;160:303-320.
13. Vidal M, Cusick ME, Barabasi AL. Interactome networks and human disease. Cell 2011;144:986-998.
14. Ideker T, Sharan R. Protein networks in disease. Genome Res 2008;18:644-652.
15. Gavin AC, et al. Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 2002;415:141-147.
16. Kar G, Gursoy A, Keskin O. Human cancer protein-protein interaction network: a structural perspective. PLoS Comput Biol 2009;5:e1000601.
17. Ryan DP, Matthews JM. Protein-protein interactions in human disease. Curr Opin Struct Biol 2005;15:441-446.
18. Zinzalla G, Thurston DE. Targeting protein-protein interactions for therapeutic intervention: a challenge for the future. Future Med Chem 2009;1:65-93.
19. Arkin M. Protein-protein interactions and cancer: small molecules going in for the kill. Curr Opin Chem Biol 2005;9:317-324.
20. Morelli X, Bourgeas R, Roche P. Chemical and structural lessons from recent successes in protein-protein interaction inhibition (2P2I). Curr Opin Chem Biol 2011;15:475-481.
21. Peloquin GL, Chen YB, Fathi AT. The evolving landscape in the therapy of acute myeloid leukemia. Protein Cell 2013;4:735-746.
22. Nero TL, Morton CJ, Holien JK, Wielens J, Parker MW. Oncogenic protein interfaces: small molecules, big challenges. Nat Rev Cancer 2014;14:248-262.
23. Wells JA, McClendon CL. Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 2007;450:1001-1009.
24. Fry DC, Vassilev LT. Targeting protein-protein interactions for cancer therapy. J Mol Med (Berl) 2005;83:955-963.
25. Arkin MR, Whitty A. The road less traveled: modulating signal transduction enzymes by inhibiting their protein-protein interactions. Curr Opin Chem Biol 2009;13:284-290.
26. Venkatesan K, et al. An empirical framework for binary interactome mapping. Nat Methods 2009;6:83-90.
27. Stumpf MP, et al. Estimating the size of the human interactome. Proc Natl Acad Sci USA 2008;105:6959-6964.
28. Zhang L, Daly RJ. Targeting the human kinome for cancer therapy: current perspectives. Crit Rev Oncog 2012;17:233-246.
29. Yokoyama A, Somervaille TC, Smith KS, Rozenblatt-Rosen O, Meyerson M, Cleary ML. The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis. Cell 2005;123:207-218.
30. Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R, Scapozza L. Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias. Lancet Oncol 2003;4:75-85.
31. O'Hare T, Eide CA, Deininger MW. Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 2007;110:2242-2249.
32. Furman RR, et al. Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med 2014;370:2352-2354.
33. Yang SH. Molecular basis of drug resistance: epidermal growth factor receptor tyrosine kinase inhibitors and anaplastic lymphoma kinase inhibitors. Tuberc Respir Dis (Seoul) 2013;75:188-198.
34. Ma B, Elkayam T, Wolfson H, Nussinov R. Protein-protein interactions: structurally conserved residues distinguish between binding sites and exposed protein surfaces. Proc Natl Acad Sci USA 2003;100:5772-5777.
35. Li X, Keskin O, Ma B, Nussinov R, Liang J. Protein-protein interactions: hot spots and structurally conserved residues often locate in complemented pockets that pre-organized in the unbound states: implications for docking. J Mol Biol 2004;344:781-795.
36. Keskin O, Ma B, Nussinov R. Hot regions in protein-protein interactions: the organization and contribution of structurally conserved hot spot residues. J Mol Biol 2005;345:1281-1294.
37. Guerois R, Nielsen JE, Serrano L. Predicting changes in the stability of proteins and protein complexes: a study of more than 1000 mutations. J Mol Biol 2002;320:369-387.
38. Jung M, et al. Affinity map of bromodomain protein 4 (BRD4) interactions with the histone H4 tail and the small molecule inhibitor JQ1. J Biol Chem 2014;289:9304-9319.
39. Jones S, Thornton JM. Principles of protein-protein interactions. Proc Natl Acad Sci USA 1996;93:13-20.
40. Lo Conte L, Chothia C, Janin J. The atomic structure of protein-protein recognition sites. J Mol Biol 1999;285:2177-2198.
41. Tsai CJ, del Sol A, Nussinov R. Allostery: absence of a change in shape does not imply that allostery is not at play. J Mol Biol 2008;378:1-11.
42. Goodey NM, Benkovic SJ. Allosteric regulation and catalysis emerge via a common route. Nat Chem Biol 2008;4:474-482.
43. Gorczynski MJ, et al. Allosteric inhibition of the protein-protein interaction between the leukemia-associated proteins Runx1 and CBFbeta. Chem Biol 2007;14:1186-1197.
44. Petsalaki E, Russell RB. Peptide-mediated interactions in biological systems: new discoveries and applications. Curr Opin Biotechnol 2008;19:344-350.
45. London N, Movshovitz-Attias D, Schueler-Furman O. The structural basis of peptide-protein binding strategies. Structure 2010;18:188-199.
46. Wright PE, Dyson HJ. Linking folding and binding. Curr Opin Struct Biol 2009;19:31-38.
47. Demarest SJ, et al. Mutual synergistic folding in recruitment of CBP/p300 by p160 nuclear receptor coactivators. Nature 2002;415:549-553.
48. Leach BI, Kuntimaddi A, Schmidt CR, Cierpicki T, Johnson SA, Bushweller JH. Leukemia fusion target AF9 is an intrinsically disordered transcriptional regulator that recruits multiple partners via coupled folding and binding. Structure 2013;21:176-183.
49. Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN. Flexible nets. The roles of intrinsic disorder in protein interaction networks. FEBS J 2005;272:5129-5148.
50. Clackson T, Wells JA. A hot spot of binding energy in a hormone-receptor interface. Science 1995;267:383-386.
51. Bogan AA, Thorn KS. Anatomy of hot spots in protein interfaces. J Mol Biol 1998;280:1-9.
52. Ma B, Nussinov R. Trp/Met/Phe hot spots in protein-protein interactions: potential targets in drug design. Curr Top Med Chem 2007;7:999-1005.
53. DeLano WL. Unraveling hot spots in binding interfaces: progress and challenges. Curr Opin Struct Biol 2002;12:14-20.
54. Moreira IS, Fernandes PA, Ramos MJ. Hot spots - a review of the protein-protein interface determinant amino-acid residues. Proteins 2007;68:803-812.
55. Zerbe BS, Hall DR, Vajda S, Whitty A, Kozakov D. Relationship between hot spot residues and ligand binding hot spots in protein-protein interfaces. J Chem Inf Model 2012;52:2236-2244.
56. Reichmann D, Rahat O, Albeck S, Meged R, Dym O, Schreiber G. The modular architecture of protein-protein binding interfaces. Proc Natl Acad Sci USA 2005;102:57-62.
57. Kozakov D, et al. Structural conservation of druggable hot spots in protein-protein interfaces. Proc Natl Acad Sci USA 2011;108:13528-13533.
58. Makley LN, Gestwicki JE. Expanding the number of 'druggable' targets: non-enzymes and protein-protein interactions. Chem Biol Drug Des 2013;81:22-32.
59. Smith MC, Gestwicki JE. Features of protein-protein interactions that translate into potent inhibitors: topology, surface area and affinity. Expert Rev Mol Med 2012;14:e16.
60. Lanzarotti E, Biekofsky RR, Estrin DA, Marti MA, Turjanski AG. Aromatic-aromatic interactions in proteins: beyond the dimer. J Chem Inf Model 2011;51:1623-1633.
61. Villoutreix BO, Labbe CM, Lagorce D, Laconde G, Sperandio O. A leap into the chemical space of protein-protein interaction inhibitors. Curr Pharm Des 2012;18:4648-4667.
62. Goh CS, Milburn D, Gerstein M. Conformational changes associated with protein-protein interactions. Curr Opin Struct Biol 2004;14:104-109.
63. Lee EF, et al. Conformational changes in Bcl-2 pro-survival proteins determine their capacity to bind ligands. J Biol Chem 2009;284:30508-30517.
64. Eyrisch S, Helms V. Transient pockets on protein surfaces involved in protein-protein interaction. J Med Chem 2007;50:3457-3464.
65. Arkin MR, et al. Binding of small molecules to an adaptive protein-protein interface. Proc Natl Acad Sci USA 2003;100:1603-1608.
66. Widmer H, Jahnke W. Protein NMR in biomedical research. Cell Mol Life Sci 2004;61:580-599.
67. Sivanesan D, Rajnarayanan RV, Doherty J, Pattabiraman N. In-silico screening using flexible ligand binding pockets: a molecular dynamics-based approach. J Comput Aided Mol Des 2005;19:213-228.
68. Caballero J, Alzate-Morales JH. Molecular dynamics of protein kinase-inhibitor complexes: a valid structural information. Curr Pharm Des 2012;18:2946-2963.
69. Lexa KW, Carlson HA. Full protein flexibility is essential for proper hot-spot mapping. J Am Chem Soc 2011;133:200-202.
70. White AW, Westwell AD, Brahemi G. Protein-protein interactions as targets for small-molecule therapeutics in cancer. Expert Rev Mol Med 2008;10:e8.
71. Vitagliano O, Addeo R, D'Angelo V, Indolfi C, Indolfi P, Casale F. The Bcl-2/Bax and Ras/Raf/MEK/ERK signaling pathways: implications in pediatric leukemia pathogenesis and new prospects for therapeutic approaches. Expert Rev Hematol 2013;6:587-597.
72. Brinkmann K, Kashkar H. Targeting the mitochondrial apoptotic pathway: a preferred approach in hematologic malignancies? Cell Death Dis 2014;5:e1098.
73. Goard CA, Schimmer AD. An evidence-based review of obatoclax mesylate in the treatment of hematological malignancies. Core Evid 2013;8:15-26.
74. Vogler M, Dinsdale D, Dyer MJ, Cohen GM. Bcl-2 inhibitors: small molecules with a big impact on cancer therapy. Cell Death Differ 2009;16:360-367.
75. Shangary S, Wang S. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy. Annu Rev Pharmacol Toxicol 2009;49:223-241.
76. Sun D, et al. Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development. J Med Chem 2014;57:1454-1472.
77. Khoo KH, Verma CS, Lane DP. Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov 2014;13:217-236.
78. Grembecka J, et al. Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nat Chem Biol 2012;8:277-284.
79. Shi A, et al. Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia. Blood 2012;120:4461-4469.
80. He S, et al. High-affinity small-molecule inhibitors of the menin-mixed lineage leukemia (MLL) interaction closely mimic a natural protein-protein interaction. J Med Chem 2014;57:1543-1556.
81. Cao F, et al. Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia. Mol Cell 2014;53:247-261.
82. Senisterra G, et al. Small-molecule inhibition of MLL activity by disruption of its interaction with WDR5. Biochem J 2013;449:151-159.
83. Cunningham L, et al. Identification of benzodiazepine Ro5-3335 as an inhibitor of CBF leukemia through quantitative high throughput screen against RUNX1-CBFbeta interaction. Proc Natl Acad Sci USA 2012;109:14592-14597.
84. Zuber J, et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 2011;478:524-528.
85. Dawson MA, et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 2011;478:529-533.
86. Delmore JE, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 2011;146:904-917.
87. Cerchietti LC, et al. A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo. Cancer Cell 2010;17:400-411.
88. Mirguet O, et al. Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains. J Med Chem 2013;56:7501-7515.
89. Marschalek R. Mechanisms of leukemogenesis by MLL fusion proteins. Br J Haematol 2011;152:141-154.
90. Tomizawa D, et al. Outcome of risk-based therapy for infant acute lymphoblastic leukemia with or without an MLL gene rearrangement, with emphasis on late effects: a final report of two consecutive studies, MLL96 and MLL98, of the Japan Infant Leukemia Study Group. Leukemia 2007;21:2258-2263.
91. Popovic R, Zeleznik-Le NJ. MLL: how complex does it get? J Cell Biochem 2005;95:234-242.
92. Hess JL. MLL: a histone methyltransferase disrupted in leukemia. Trends Mol Med 2004;10:500-507.
93. Krivtsov AV, Armstrong SA. MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer 2007;7:823-833.
94. Slany RK. The molecular biology of mixed lineage leukemia. Haematologica 2009;94:984-993.
95. Slany RK. When epigenetics kills: MLL fusion proteins in leukemia. Hematol Oncol 2005;23:1-9.
96. Dimartino JF, Cleary ML. Mll rearrangements in haematological malignancies: lessons from clinical and biological studies. Br J Haematol 1999;106:614-626.
97. Daigle SR, et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood 2013;122:1017-1025.
98. Knapper S. FLT3 inhibition in acute myeloid leukaemia. Br J Haematol 2007;138:687-699.
99. Wang Z, Smith KS, Murphy M, Piloto O, Somervaille TC, Cleary ML. Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy. Nature 2008;455:1205-1209.
100. Placke T, et al. Requirement for CDK6 in MLL-rearranged acute myeloid leukemia. Blood 2014;124:13-23.
101. Ayton PM, Cleary ML. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene 2001;20:5695-5707.
102. Dou Y, et al. Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell 2005;121:873-885.
103. Milne TA, et al. MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell 2002;10:1107-1117.
104. Thiel AT, et al. MLL-AF9-induced leukemogenesis requires coexpression of the wild-type Mll allele. Cancer Cell 2010;17:148-159.
105. Dou Y, et al. Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nat Struct Mol Biol 2006;13:713-719.
106. Song JJ, Kingston RE. WDR5 interacts with mixed lineage leukemia (MLL) protein via the histone H3-binding pocket. J Biol Chem 2008;283:35258-35264.
107. Yokoyama A, Cleary ML. Menin critically links MLL proteins with LEDGF on cancer-associated target genes. Cancer Cell 2008;14:36-46.
108. Cierpicki T, Grembecka J. Challenges and opportunities in targeting the menin-MLL interaction. Future Med Chem 2014;6:447-462.
109. Grembecka J, Belcher AM, Hartley T, Cierpicki T. Molecular basis of the mixed lineage leukemia-menin interaction: implications for targeting mixed lineage leukemias. J Biol Chem 2010;285:40690-40698.
110. Murai MJ, Chruszcz M, Reddy G, Grembecka J, Cierpicki T. Crystal structure of menin reveals binding site for mixed lineage leukemia (MLL) protein. J Biol Chem 2011;286:31742-31748.
111. Huang J, et al. The same pocket in menin binds both MLL and JUND but has opposite effects on transcription. Nature 2012;482:542-546.
112. Zhou H, et al. Structure-based design of high-affinity macrocyclic peptidomimetics to block the menin-mixed lineage leukemia 1 (MLL1) protein-protein interaction. J Med Chem 2013;56:1113-1123.
113. Patel A, Dharmarajan V, Cosgrove MS. Structure of WDR5 bound to mixed lineage leukemia protein-1 peptide. J Biol Chem 2008;283:32158-32161.
114. Karatas H, Townsend EC, Bernard D, Dou Y, Wang S. Analysis of the binding of mixed lineage leukemia 1 (MLL1) and histone 3 peptides to WD repeat domain 5 (WDR5) for the design of inhibitors of the MLL1-WDR5 interaction. J Med Chem 2010;53:5179-5185.
115. Bolshan Y, et al. Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5-MLL Interaction. ACS Med Chem Lett 2013;4:353-357.
116. Karatas H, et al. High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction. J Am Chem Soc 2013;135:669-682.
117. McCabe MT, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 2012;492:108-112.
118. Knutson SK, et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol 2012;8:890-896.
119. Kim W, et al. Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer. Nat Chem Biol 2013;9:643-650.
120. Liu P, et al. Fusion between transcription factor CBF beta/PEBP2 beta and a myosin heavy chain in acute myeloid leukemia. Science 1993;261:1041-1044.
121. Castilla LH, et al. Failure of embryonic hematopoiesis and lethal hemorrhages in mouse embryos heterozygous for a knocked-in leukemia gene CBFB-MYH11. Cell 1996;87:687-696.
122. Lukasik SM, et al. Altered affinity of CBF beta-SMMHC for Runx1 explains its role in leukemogenesis. Nat Struct Biol 2002;9:674-679.
123. Warren AJ, Bravo J, Williams RL, Rabbitts TH. Structural basis for the heterodimeric interaction between the acute leukaemia-associated transcription factors AML1 and CBFbeta. EMBO J 2000;19:3004-3015.
124. Tahirov TH, et al. Structural analyses of DNA recognition by the AML1/Runx-1 Runt domain and its allosteric control by CBFbeta. Cell 2001;104:755-767.
125. Tang YY, et al. Energetic and functional contribution of residues in the core binding factor beta (CBFbeta) subunit to heterodimerization with CBFalpha. J Biol Chem 2000;275:39579-39588.
126. Bushweller JH, et al. A small molecule inhibitor of the CBFb-SMMHC/RUNX interaction attenuates inv(16) leukemia in vivo. Blood 2012;120:286.
127. Marushige K. Activation of chromatin by acetylation of histone side chains. Proc Natl Acad Sci USA 1976;73:3937-3941.
128. Filippakopoulos P, et al. Selective inhibition of BET bromodomains. Nature 2010;468:1067-1073.
129. Filippakopoulos P, Knapp S. Targeting bromo-domains: epigenetic readers of lysine acetylation. Nat Rev Drug Discov 2014;13:337-356.
130. Liu Y, et al. Structural basis and binding properties of the second bromodomain of Brd4 with acetylated histone tails. Biochemistry 2008;47:6403-6417.
131. Filippakopoulos P, et al. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell 2012;149:214-231.
132. Nicodeme E, et al. Suppression of inflammation by a synthetic histone mimic. Nature 2010;468:1119-1123.
133. Ye BH. BCL-6 in the pathogenesis of non-Hodgkin's lymphoma. Cancer Invest 2000;18:356-365.
134. Cerchietti LC, et al. A peptomimetic inhibitor of BCL6 with potent antilymphoma effects in vitro and in vivo. Blood 2009;113:3397-3405.
135. Polo JM, et al. Specific peptide interference reveals BCL6 transcriptional and oncogenic mechanisms in B-cell lymphoma cells. Nat Med 2004;10:1329-1335.
136. Ghetu AF, Corcoran CM, Cerchietti L, Bardwell VJ, Melnick A, Prive GG. Structure of a BCOR corepressor peptide in complex with the BCL6 BTB domain dimer. Mol Cell 2008;29:384-391.
137. Ahmad KF, et al. Mechanism of SMRT corepressor recruitment by the BCL6 BTB domain. Mol Cell 2003;12:1551-1564.
138. Fry DC. Protein-protein interactions as targets for small molecule drug discovery. Biopolymers 2006;84:535-552.
139. Pagliaro L, et al. Emerging classes of protein-protein interaction inhibitors and new tools for their development. Curr Opin Chem Biol 2004;8:442-449.
140. Toogood PL. Inhibition of protein-protein association by small molecules: approaches and progress. J Med Chem 2002;45:1543-1558.
141. Loregian A, Palu G. Disruption of protein-protein interactions: towards new targets for chemotherapy. J Cell Physiol 2005;204:750-762.
142. Moerke NJ, et al. Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G. Cell 2007;128:257-267.
143. Inglese J, et al. High-throughput screening assays for the identification of chemical probes. Nat Chem Biol 2007;3:466-479.
144. Gotoh Y, Nagata H, Kase H, Shimonishi M, Ido M. A homogeneous time-resolved fluorescence-based high-throughput screening system for discovery of inhibitors of IKKbeta-NEMO interaction. Anal Biochem 2010;405:19-27.
145. Glickman JF, et al. A comparison of ALPHAScreen, TR-FRET, and TRF as assay methods for FXR nuclear receptors. J Biomol Screen 2002;7:3-10.
146. Bauer RA, Wurst JM, Tan DS. Expanding the range of 'druggable' targets with natural product-based libraries: an academic perspective. Curr Opin Chem Biol 2010;14:308-314.
147. Dandapani S, Marcaurelle LA. Grand challenge commentary: accessing new chemical space for 'undruggable' targets. Nat Chem Biol 2010;6:861-863.
148. Galloway WR, Isidro-Llobet A, Spring DR. Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules. Nat Commun 2010;1:80.
149. Burke MD, Schreiber SL. A planning strategy for diversity-oriented synthesis. Angew Chem Int Ed Engl 2004;43:46-58.
150. Boldi AM. Libraries from natural product-like scaffolds. Curr Opin Chem Biol 2004;8:281-286.
151. Koehn FE, Carter GT. The evolving role of natural products in drug discovery. Nat Rev Drug Discov 2005;4:206-220.
152. Larsen MJ, et al. The role of HTS in drug discovery at the University of Michigan. Comb Chem High Throughput Screen 2014;17:210-230.
153. De Clercq E. The design of drugs for HIV and HCV. Nat Rev Drug Discov 2007;6:1001-1018.
154. Sakurai K, Chung HS, Kahne D. Use of a retroinverso p53 peptide as an inhibitor of MDM2. J Am Chem Soc 2004;126:16288-16289.
155. Zhong S, Macias AT, MacKerell AD Jr. Computational identification of inhibitors of protein-protein interactions. Curr Top Med Chem 2007;7:63-82.
156. Falchi F, Caporuscio F, Recanatini M. Structure-based design of small-molecule protein-protein interaction modulators: the story so far. Future Med Chem 2014;6:343-357.
157. Siddiquee K, et al. Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci USA 2007;104:7391-7396.
158. Song H, Wang R, Wang S, Lin J. A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast cancer cells. Proc Natl Acad Sci USA 2005;102:4700-4705.
159. Renaud JP, Delsuc MA. Biophysical techniques for ligand screening and drug design. Curr Opin Pharmacol 2009;9:622-628.
160. Murray CW, Rees DC. The rise of fragment-based drug discovery. Nat Chem 2009;1:187-192.
161. Tse C, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 2008;68:3421-3428.
162. Schuffenhauer A, et al. Library design for fragment based screening. Curr Top Med Chem 2005;5:751-762.
163. Scott DE, Coyne AG, Hudson SA, Abell C. Fragment-based approaches in drug discovery and chemical biology. Biochemistry 2012;51:4990-5003.
164. Kumar A, Voet A, Zhang KY. Fragment based drug design: from experimental to computational approaches. Curr Med Chem 2012;19:5128-5147.
165. Oltersdorf T, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005;435:677-681.
166. Wendt MD, et al. Discovery and structure-activity relationship of antagonists of B-cell lymphoma 2 family proteins with chemopotentiation activity in vitro and in vivo. J Med Chem 2006;49:1165-1181.
167. Park CM, et al. Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins. J Med Chem 2008;51:6902-6915.
168. Friberg A, et al. Discovery of potent myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods and structure-based design. J Med Chem 2013;56:15-30.
169. Huang JW, et al. Fragment-based design of small molecule X-linked inhibitor of apoptosis protein inhibitors. J Med Chem 2008;51:7111-7118.
170. Leach AR, Hann MM. Molecular complexity and fragment-based drug discovery: ten years on. Curr Opin Chem Biol 2011;15:489-496.
171. Moriniere J, et al. Cooperative binding of two acetylation marks on a histone tail by a single bromodomain. Nature 2009;461:664-668.
172. Ku B, Liang C, Jung JU, Oh BH. Evidence that inhibition of BAX activation by BCL-2 involves its tight and preferential interaction with the BH3 domain of BAX. Cell Res 2011;21:627-641.
173. Dunker AK, Silman I, Uversky VN, Sussman JL. Function and structure of inherently disordered proteins. Curr Opin Struct Biol 2008;18:756-764.
174. Chen CY, Tou WI. How to design a drug for the disordered proteins? Drug Discov Today 2013;18:910-915.
175. Muntean AG, Hess JL. The pathogenesis of mixed-lineage leukemia. Annu Rev Pathol 2012;7:283-301.
176. Palermo CM, Bennett CA, Winters AC, Hemenway CS. The AF4-mimetic peptide, PFWT, induces necrotic cell death in MV4-11 leukemia cells. Leuk Res 2008;32:633-642.
177. Feng BY, Shelat A, Doman TN, Guy RK, Shoichet BK. High-throughput assays for promiscuous inhibitors. Nat Chem Biol 2005;1:146-148.
178. Shoichet BK. Screening in a spirit haunted world. Drug Discov Today 2006;11:607-615.
179. Pellecchia M, et al. Perspectives on NMR in drug discovery: a technique comes of age. Nat Rev Drug Discov 2008;7:738-745.
180. Chaires JB. Calorimetry and thermodynamics in drug design. Annu Rev Biophys 2008;37:135-151.
181. Cooper MA. Optical biosensors in drug discovery. Nat Rev Drug Discov 2002;1:515-528.
182. Stevens AJ, Jensen JJ, Wyller K, Kilgore PC, Chatterjee S, Rohrbaugh ML. The role of public-sector research in the discovery of drugs and vaccines. N Engl J Med 2011;364:535-541.
183. Frye S, Crosby M, Edwards T, Juliano R. US academic drug discovery. Nat Rev Drug Discov 2011;10:409-410.
184. Fishburn CS. Translational research: the changing landscape of drug discovery. Drug Discov Today 2013;18:487-494.
185. Schultz-Kirkegaard H, Valentin F. Academic drug discovery centres: the economic and organisational sustainability of an emerging model. Drug Discov Today 2014; pii:S1359-6446(14)00245-1.
186. Coles LD, Cloyd JC. The role of academic institutions in the development of drugs for rare and neglected diseases. Clin Pharmacol Ther 2012;92:193-202.
187. Whitty A, Kumaravel G. Between a rock and a hard place? Nat Chem Biol 2006;2:112-118.
188. Arkin MR, Wells JA. Small-molecule inhibitors of protein-protein interactions: progressing towards the dream. Nat Rev Drug Discov 2004;3:301-317.
189. Berg T. Small-molecule inhibitors of protein-protein interactions. Curr Opin Drug Discov Devel 2008;11:666-674.
190. Lipinski CA. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol 2004;1:337-341.
191. Huber W, Mueller F. Biomolecular interaction analysis in drug discovery using surface plasmon resonance technology. Curr Pharm Des 2006;12:3999-4021.
192. Frank AO, et al. Discovery of a potent inhibitor of replication protein a protein-protein interactions using a fragment-linking approach. J Med Chem 2013;56:9242-9250.
193. Sun Q, et al. Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation. Angew Chem Int Ed Engl 2012;51:6140-6143.
194. Vu B, et al. Discovery of RG7112: a small-molecule MDM2 inhibitor in clinical development. ACS Med Chem Lett 2013;4:466-469.
195. Emami KH, et al. A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. Proc Natl Acad Sci USA 2004;101:12682-12687.
196. Condon SM, et al. Birinapant, a smac-mimetic with improved tolerability for the treatment of solid tumors and hematological malignancies. J Med Chem 2014;57:3666-3677.
197. Houghton PJ, et al. Initial testing (stage 1) of LCL161, a SMAC mimetic, by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer 2012;58:636-639.
198. Gandhi L, et al. Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. J Clin Oncol 2011;29:909-916.
199. Schimmer AD, et al. A phase I study of the pan bcl-2 family inhibitor obatoclax mesylate in patients with advanced hematologic malignancies. Clin Cancer Res 2008;14:8295-8301.
200. Basse MJ, et al. 2P2Idb: a structural database dedicated to orthosteric modulation of protein-protein interactions. Nucleic Acids Res 2013;41:D824-D827.