Targeting protein-protein interaction by small molecules

Annual Review of Pharmacology and Toxicology

Volumn 54, Issue , 2014, Pages 435-456

  Jin, Lingyan ^a   Wang, Weiru ^a   Fang, Guowei ^a,b  

^a GENENTECH INC   (United States)

^b ABBVIE INC   (United States)

Author keywords

Allosteric inhibitors; Interfacial binders; Orthosteric inhibitors; PPIs; Protein protein interactions; Small molecule inhibitors

Indexed keywords

ARF PROTEIN; B RAF KINASE; B RAF KINASE INHIBITOR; MIXED LINEAGE LEUKEMIA PROTEIN; PROTEIN KINASE B INHIBITOR; RAS PROTEIN; SMALL MOLECULE TRANSPORT AGENT; SOS PROTEIN;

ALLOSTERISM; HUMAN; MOLECULAR LIBRARY; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN PROTEIN INTERACTION; REVIEW;

CARRIER PROTEINS; HUMANS; MEMBRANE PROTEINS; MODELS, MOLECULAR; MOLECULAR TARGETED THERAPY; PROTEIN BINDING; PROTEIN INTERACTION DOMAINS AND MOTIFS; PROTO-ONCOGENE PROTEINS B-RAF; PROTO-ONCOGENE PROTEINS C-AKT; RAS PROTEINS; SOS1 PROTEIN; THYROID HORMONES;

EID: 84891850975     PISSN: 03621642     EISSN: 15454304     Source Type: Book Series    
DOI: 10.1146/annurev-pharmtox-011613-140028     Document Type: Review

References (119)

1. Drews J. 1996. Genomic sciences and the medicine of tomorrow. Nat. Biotechnol. 14:1516-18
2. Drews J, Ryser S. 1997. The role of innovation in drug development. Nat. Biotechnol. 15:1318-19
3. Hopkins AL, Groom CR. 2002. The druggable genome. Nat. Rev. Drug Discov. 1:727-30
4. Cheng AC, Coleman RG, Smyth KT, Cao Q, Soulard P, et al. 2007. Structure-based maximal affinity model predicts small-molecule druggability. Nat. Biotechnol. 25:71-75
5. Wells JA, McClendon CL. 2007. Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 450:1001-9
6. Hajduk PJ, Huth JR, Tse C. 2005. Predicting protein druggability. Drug Discov. Today 10:1675-82
7. Huang N, Jacobson MP. 2010. Binding-site assessment by virtual fragment screening. PLoS ONE 5:e10109
8. Braisted AC, Oslob JD, Delano WL, Hyde J, McDowell RS, et al. 2003. Discovery of a potent small molecule IL-2 inhibitor through fragment assembly. J. Am. Chem. Soc. 125:3714-15
9. Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, et al. 2005. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435:677-81
10. Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, et al. 2008. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 68:3421-28
11. Vassilev LT. 2004. Small-molecule antagonists of p53-MDM2 binding: research tools and potential therapeutics. Cell Cycle 3:419-21
12. Grasberger BL, Lu T, Schubert C, Parks DJ, Carver TE, et al. 2005. Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells. J. Med. Chem. 48:909-12
13. Flygare JA, Beresini M, Budha N, Chan H, Chan IT, et al. 2012. Discovery of a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins and clinical candidate for the treatment of cancer (GDC-0152). J. Med. Chem. 55:4101-13
14. Cohen F, Koehler MF, Bergeron P, Elliott LO, Flygare JA, et al. 2010. Antagonists of inhibitor of apoptosis proteins based on thiazole amide isosteres. Bioorg. Med. Chem. Lett. 20:2229-33
15. Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, et al. 2010. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467:596-99
16. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, et al. 2010. RAF inhibitors prime wildtype RAF to activate the MAPK pathway and enhance growth. Nature 464:431-35
17. Mossessova E, Corpina RA, Goldberg J. 2003. Crystal structure of ARF1•Sec7 complexedwithBrefeldin A and its implications for the guanine nucleotide exchange mechanism. Mol. Cell 12:1403-11
18. Mattmann ME, Stoops SL, Lindsley CW. 2011. Inhibition of Akt with small molecules and biologics: historical perspective and current status of the patent landscape. Expert Opin. Ther. Pat. 21:1309-38
19. Anastasiou D, Yu Y, Israelsen WJ, Jiang JK, Boxer MB, et al. 2012. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat. Chem. Biol. 8:839-47
20. Vetter IR, Wittinghofer A. 2001. The guanine nucleotide-binding switch in three dimensions. Science 294:1299-304
21. Schubbert S, Bollag G, Lyubynska N, Nguyen H, Kratz CP, et al. 2007. Biochemical and functional characterization of germ line KRAS mutations. Mol. Cell. Biol. 27:7765-70
22. Boguski MS, McCormick F. 1993. Proteins regulating Ras and its relatives. Nature 366:643-54
23. Chardin P, Camonis JH, Gale NW, van Aelst L, Schlessinger J, et al. 1993. Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science 260:1338-43
24. Donovan S, Shannon KM, Bollag G. 2002. GTPase activating proteins: critical regulators of intracellular signaling. Biochim. Biophys. Acta 1602:23-45
25. Schubbert S, Shannon K, Bollag G. 2007. Hyperactive Ras in developmental disorders and cancer. Nat. Rev. Cancer 7:295-308
26. Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, et al. 2012. OncogenicKrasmaintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149:656-70
27. Tran PT, Fan AC, Bendapudi PK, Koh S, Komatsubara K, et al. 2008. Combined inactivation of MYC and K-Ras oncogenes reverses tumorigenesis in lung adenocarcinomas and lymphomas. PLoS ONE 3:e2125
28. Tanaka T, Williams RL, Rabbitts TH. 2007. Tumour prevention by a single antibody domain targeting the interaction of signal transduction proteins with RAS. EMBO J. 26:3250-59
29. Maurer T, Garrenton LS, Oh A, Pitts K, Anderson DJ, et al. 2012. Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc. Natl. Acad. Sci. USA 109:5299-304
30. Sun Q, Burke JP, Phan J, Burns MC, Olejniczak ET, et al. 2012. Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation. Angew. Chem. 51:6140-43
31. Huret JL, Dessen P, Bernheim A. 2001. An atlas of chromosomes in hematological malignancies. Example: 11q23 and MLL partners. Leukemia 15:987-89
32. Sorensen PH, Chen CS, Smith FO, Arthur DC, Domer PH, et al. 1994. Molecular rearrangements of the MLL gene are present in most cases of infant acute myeloid leukemia and are strongly correlated with monocytic or myelomonocytic phenotypes. J. Clin. Investig. 93:429-37
33. Hess JL. 2004. MLL: a histone methyltransferase disrupted in leukemia. Trends Mol. Med. 10:500-7
34. Krivtsov AV, Armstrong SA. 2007. MLL translocations, histone modifications and leukaemia stem-cell development. Nat. Rev. Cancer 7:823-33
35. Lawrence HJ, Helgason CD, Sauvageau G, Fong S, Izon DJ, et al. 1997. Mice bearing a targeted interruption of the homeobox gene HOXA9 have defects in myeloid, erythroid, and lymphoid hematopoiesis. Blood 89:1922-30
36. Yokoyama A, Lin M, Naresh A, Kitabayashi I, Cleary ML. 2010. A higher-order complex containing AF4 and ENL family proteins with P-TEFb facilitates oncogenic and physiologic MLL-dependent transcription. Cancer Cell 17:198-212
37. Argiropoulos B, Palmqvist L, Yung E, Kuchenbauer F, Heuser M, et al. 2008. Linkage of Meis1 leukemogenic activity to multiple downstream effectors including Trib2 and Ccl3. Exp. Hematol. 36:845-59
38. Wong P, Iwasaki M, Somervaille TC, So CW, Cleary ML. 2007. Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential. Genes Dev. 21:2762-74
39. Zeisig BB, Milne T, Garcia-Cuellar MP, Schreiner S, Martin ME, et al. 2004. Hoxa9 and Meis1 are key targets for MLL-ENL-mediated cellular immortalization. Mol. Cell. Biol. 24:617-28
40. Ayton PM, Cleary ML. 2003. Transformation of myeloid progenitors byMLLoncoproteins is dependent on Hoxa7 and Hoxa9. Genes Dev. 17:2298-307
41. Rozovskaia T, Feinstein E, Mor O, Foa R, Blechman J, et al. 2001. Upregulation of Meis1 and HoxA9 in acute lymphocytic leukemias with the t(4 : 11) abnormality. Oncogene 20:874-78
42. Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, et al. 1997. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276:404-7
43. Yokoyama A, Somervaille TC, Smith KS, Rozenblatt-Rosen O, Meyerson M, Cleary ML. 2005. The menin tumor suppressor protein is an essential oncogenic cofactor forMLL-associated leukemogenesis. Cell 123:207-18
44. Yokoyama A, Wang Z, Wysocka J, Sanyal M, Aufiero DJ, et al. 2004. Leukemia proto-oncoproteinMLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression. Mol. Cell. Biol. 24:5639-49
45. Shi A, Murai MJ, He S, Lund G, Hartley T, et al. 2012. Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia. Blood 120:4461-69
46. Grembecka J, Belcher AM, Hartley T, Cierpicki T. 2010. Molecular basis of the mixed lineage leukemiamenin interaction: implications for targeting mixed lineage leukemias. J. Biol. Chem. 285:40690-98
47. Huang J, Gurung B, Wan B, Matkar S, Veniaminova NA, et al. 2012. The same pocket in menin binds both MLL and JUND but has opposite effects on transcription. Nature 482:542-46
48. Grembecka J, He S, Shi A, Purohit T, Muntean AG, et al. 2012. Menin-MLLinhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nat. Chem. Biol. 8:277-84
49. French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA. 2003. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res. 63:304-7
50. French CA, Miyoshi I, Aster JC, Kubonishi I, Kroll TG, et al. 2001. BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19). Am. J. Pathol. 159:1987-92
51. French CA, Ramirez CL, Kolmakova J, Hickman TT, Cameron MJ, et al. 2008. BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene 27:2237-42
52. Zuber J, Rappaport AR, Luo W, Wang E, Chen C, et al. 2011. An integrated approach to dissecting oncogene addiction implicates a Myb-coordinated self-renewal program as essential for leukemia maintenance. Genes Dev. 25:1628-40
53. Dawson MA, Prinjha RK, Dittmann A, Giotopoulos G, Bantscheff M, et al. 2011. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478:529-33
54. Yang Z, Yik JH, Chen R, He N, Jang MK, et al. 2005. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol. Cell 19:535-45
55. Yang Z, He N, Zhou Q. 2008. Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progression. Mol. Cell. Biol. 28:967-76
56. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, et al. 2011. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146:904-17
57. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, et al. 2010. The landscape of somatic copy-number alteration across human cancers. Nature 463:899-905
58. Jain M, Arvanitis C, Chu K, Dewey W, Leonhardt E, et al. 2002. Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science 297:102-4
59. Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, et al. 2010. Selective inhibition of BET bromodomains. Nature 468:1067-73
60. Chung CW, Coste H, White JH, Mirguet O, Wilde J, et al. 2011. Discovery and characterization of small molecule inhibitors of the BET family bromodomains. J. Med. Chem. 54:3827-38
61. Filippakopoulos P, Picaud S, Mangos M, Keates T, Lambert JP, et al. 2012. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell 149:214-31
62. Lippincott-Schwartz J, Donaldson JG, Schweizer A, Berger EG, Hauri HP, et al. 1990. Microtubuledependent retrograde transport of proteins into the ER in the presence of brefeldin A suggests an ER recycling pathway. Cell 60:821-36
63. Donaldson JG, Cassel D, Kahn RA, Klausner RD. 1992. ADP-ribosylation factor, a small GTP-binding protein, is required for binding of the coatomer protein β-COP to Golgi membranes. Proc. Natl. Acad. Sci. USA 89:6408-12
64. Helms JB, Rothman JE. 1992. Inhibition by brefeldin A of a Golgi membrane enzyme that catalyses exchange of guanine nucleotide bound to ARF. Nature 360:352-54
65. Pasqualato S, Renault L, Cherfils J. 2002. Arf, Arl, Arp and Sar proteins: a family of GTP-binding proteins with a structural device for 'front-back' communication. EMBO Rep. 3:1035-41
66. Szul T, Grabski R, Lyons S, Morohashi Y, Shestopal S, et al. 2007. Dissecting the role of the ARF guanine nucleotide exchange factor GBF1 in Golgi biogenesis and protein trafficking. J. Cell Sci. 120:3929-40
67. Renault L, Guibert B, Cherfils J. 2003. Structural snapshots of the mechanism and inhibition of a guanine nucleotide exchange factor. Nature 426:525-30
68. Peyroche A, Antonny B, Robineau S, Acker J, Cherfils J, Jackson CL. 1999. Brefeldin A acts to stabilize an abortive ARF-GDP-Sec7 domain protein complex: involvement of specific residues of the Sec7 domain. Mol. Cell 3:275-85
69. Ravelli RB, Gigant B, Curmi PA, Jourdain I, Lachkar S, et al. 2004. Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature 428:198-202
70. Gigant B, Wang C, Ravelli RB, Roussi F, Steinmetz MO, et al. 2005. Structural basis for the regulation of tubulin by vinblastine. Nature 435:519-22
71. Choi J, Chen J, Schreiber SL, Clardy J. 1996. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 273:239-42
72. Wellbrock C, Karasarides M, Marais R. 2004. The RAF proteins take centre stage. Nat. Rev. Mol. Cell Biol. 5:875-85
73. Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, et al. 2010. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140:209-21
74. Gray-Schopfer V, Wellbrock C, Marais R. 2007. Melanoma biology and new targeted therapy. Nature 445:851-57
75. Rushworth LK, Hindley AD, O'Neill E, Kolch W. 2006. Regulation and role of Raf-1/B-Raf heterodimerization. Mol. Cell. Biol. 26:2262-72
76. Garnett MJ, Rana S, Paterson H, Barford D, Marais R. 2005. Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Mol. Cell 20:963-69
77. Weber CK, Slupsky JR, Kalmes HA, Rapp UR. 2001. Active Ras induces heterodimerization of cRaf and BRaf. Cancer Res. 61:3595-98
78. Hu J, Stites EC, Yu H, Germino EA, Meharena HS, et al. 2013. Allosteric activation of functionally asymmetric RAF kinase dimers. Cell 154:1036-46
79. Rajakulendran T, Sahmi M, Lefrancois M, Sicheri F, Therrien M. 2009. A dimerization-dependent mechanism drives RAF catalytic activation. Nature 461:542-45
80. Tsai J, Lee JT, Wang W, Zhang J, Cho H, et al. 2008. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc. Natl. Acad. Sci. USA 105:3041-46
81. King AJ, Patrick DR, Batorsky RS, Ho ML, Do HT, et al. 2006. Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. Cancer Res. 66:11100-5
82. Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, et al. 2004. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116:855-67
83. Endicott JA, Noble MEM, Johnson LN. 2012. The structural basis for control of eukaryotic protein kinases. Annu. Rev. Biochem. 81:587-613
84. Warburg O, Wind F, Negelein E. 1927. Themetabolism of tumors in the body. J. Gen. Physiol. 8:519-30
85. Koppenol WH, Bounds PL, Dang CV. 2011. Otto Warburg's contributions to current concepts of cancer metabolism. Nat. Rev. Cancer 11:325-37
86. Cairns RA, Harris IS, Mak TW. 2011. Regulation of cancer cell metabolism. Nat. Rev. Cancer 11:85-95
87. Vander Heiden MG, Cantley LC, Thompson CB. 2009. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029-33
88. Christofk HR, VanderHeiden MG, Harris MH, Ramanathan A, Gerszten RE, et al. 2008. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452:230-33
89. vanVeelen CW, Verbiest H, Zulch KJ, van Ketel BA, van der Vlist MJ, et al. 1979. L-α-alanine inhibition of pyruvate kinase from tumors of the human central nervous system. Cancer Res. 39:4263-69
90. van Veelen CW, Verbiest H, Vlug AM, Rijksen G, Staal GE. 1978. Isozymes of pyruvate kinase from human brain, meningiomas, and malignant gliomas. Cancer Res. 38:4681-87
91. Jurica MS, Mesecar A, Heath PJ, Shi W, Nowak T, Stoddard BL. 1998. The allosteric regulation of pyruvate kinase by fructose-1,6-bisphosphate. Structure 6:195-210
92. Ashizawa K, Willingham MC, Liang CM, Cheng SY. 1991. In vivo regulation of monomer-tetramer conversion of pyruvate kinase subtype M2 by glucose is mediated via fructose 1,6-bisphosphate. J. Biol. Chem. 266:16842-46
93. Jiang JK, Boxer MB, Vander Heiden MG, Shen M, Skoumbourdis AP, et al. 2010. Evaluation of thieno[3,2-b]pyrrole[3,2-d]pyridazinones as activators of the tumor cell specific M2 isoform of pyruvate kinase. Bioorg. Med. Chem. Lett. 20:3387-93
94. Boxer MB, Jiang JK, Vander Heiden MG, Shen M, Skoumbourdis AP, et al. 2010. Evaluation of substituted N, N′-diarylsulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase. J. Med. Chem. 53:1048-55
95. Vander Heiden MG, Christofk HR, Schuman E, Subtelny AO, Sharfi H, et al. 2010. Identification of small molecule inhibitors of pyruvate kinase M2. Biochem. Pharmacol. 79:1118-24
96. Cheng JQ, Lindsley CW, Cheng GZ, Yang H, Nicosia SV. 2005. The Akt/PKB pathway: molecular target for cancer drug discovery. Oncogene 24:7482-92
97. Parikh C, Janakiraman V, Wu WI, Foo CK, Kljavin NM, et al. 2012. Disruption of PH-kinase domain interactions leads to oncogenic activation of AKTin human cancers. Proc. Natl. Acad. Sci. USA 109:19368-73
98. Bilodeau MT, Balitza AE, Hoffman JM, Manley PJ, Barnett SF, et al. 2008. Allosteric inhibitors of Akt1 and Akt2: a naphthyridinone with efficacy in an A2780 tumor xenograft model. Bioorg. Med. Chem. Lett. 18:3178-82
99. Wu Z, Robinson RG, Fu S, Barnett SF, Defeo-Jones D, et al. 2008. Rapid assembly of diverse and potent allosteric Akt inhibitors. Bioorg. Med. Chem. Lett. 18:2211-14
100. Zhao Z, Robinson RG, Barnett SF, Defeo-Jones D, Jones RE, et al. 2008. Development of potent, allosteric dual Akt1 and Akt2 inhibitors with improved physical properties and cell activity. Bioorg. Med. Chem. Lett. 18:49-53
101. Lindsley CW, Zhao Z, Leister WH, Robinson RG, Barnett SF, et al. 2005. Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors. Bioorg. Med. Chem. Lett. 15:761-64
102. Wu WI, Voegtli WC, Sturgis HL, Dizon FP, Vigers GP, Brandhuber BJ. 2010. Crystal structure of human AKT1 with an allosteric inhibitor reveals a new mode of kinase inhibition. PLoS ONE 5:e12913
103. Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi S, et al. 2010. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol. Cancer Ther. 9(7):1956-67
104. Baker M. 2013. Fragment-based lead discovery grows up. Nat. Rev. Drug Discov. 12:5-7
105. Hubbard RE, Murray JB. 2011. Experiences in fragment-based lead discovery. Methods Enzymol. 493:509-31
106. Bauer RA, Wurst JM, Tan DS. 2010. Expanding the range of 'druggable' targets with natural productbased libraries: an academic perspective. Curr. Opin. Chem. Biol. 14:308-14
107. Driggers EM, Hale SP, Lee J, Terrett NK. 2008. The exploration of macrocycles for drug discovery-an underexploited structural class. Nat. Rev. Drug Discov. 7:608-24
108. Schmidt DR, Kwon O, Schreiber SL. 2004. Macrolactones in diversity-oriented synthesis: preparation of a pilot library and exploration of factors controlling macrocyclization. J. Comb. Chem. 6:286-92
109. Gartner ZJ, Tse BN, Grubina R, Doyon JB, Snyder TM, Liu DR. 2004. DNA-templated organic synthesis and selection of a library of macrocycles. Science 305:1601-5
110. Georghiou G, Kleiner RE, Pulkoski-Gross M, Liu DR, Seeliger MA. 2012. Highly specific, bisubstrate competitive Src inhibitors from DNA-templated macrocycles. Nat. Chem. Biol. 8:366-74
111. Verdine GL, Hilinski GJ. 2012. Stapled peptides for intracellular drug targets. Methods Enzymol. 503:3-33
112. LaBelle JL, Katz SG, Bird GH, Gavathiotis E, Stewart ML, et al. 2012. A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers. J. Clin. Investig. 122:2018-31
113. Walensky LD, Kung AL, Escher I, Malia TJ, Barbuto S, et al. 2004. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science 305:1466-70
114. + cytolytic T cells, show increased tumor cell apoptosis, and have lower Bcl-2 expression than diffuse large-B-cell lymphomas. Am. J. Pathol. 153:1707-15
115. Bernal F, Wade M, Godes M, Davis TN, Whitehead DG, et al. 2010. A stapled p53 helix overcomes HDMX-mediated suppression of p53. Cancer Cell 18:411-22
116. Grossmann TN, Yeh JT, Bowman BR, Chu Q, Moellering RE, Verdine GL. 2012. Inhibition of oncogenic Wnt signaling through direct targeting of β-catenin. Proc. Natl. Acad. Sci. USA 109:17942-47
117. Moellering RE, Cornejo M, Davis TN, Del Bianco C, Aster JC, et al. 2009. Direct inhibition of the NOTCH transcription factor complex. Nature 462:182-88
118. Whelan J. 2004. Stapled peptide induces cancer cell death. Drug Discov. Today 9:907
119. Clark AM, Labute P, Santavy M. 2006. 2D structure depiction. J. Chem. Inf. Model. 46:1107-23