1. Overview of Protein-Protein Interactions and Small-Molecule Inhibitors Under Clinical Development

go back to reference Arkin MR, Wells JA (2004) Small-molecule inhibitors of protein-protein interactions: progressing towards the dream. Nat Rev Drug Discov 3(4):301–317PubMedCrossRef Arkin MR, Wells JA (2004) Small-molecule inhibitors of protein-protein interactions: progressing towards the dream. Nat Rev Drug Discov 3(4):301–317PubMedCrossRef

go back to reference Stumpf MP, Thorne T, de Silva E, Stewart R, An HJ, Lappe M, Wiuf C (2008) Estimating the size of the human interactome. Proc Natl Acad Sci USA 105(19):6959–6964PubMedPubMedCentralCrossRef Stumpf MP, Thorne T, de Silva E, Stewart R, An HJ, Lappe M, Wiuf C (2008) Estimating the size of the human interactome. Proc Natl Acad Sci USA 105(19):6959–6964PubMedPubMedCentralCrossRef

go back to reference Venkatesan K, Rual JF, Vazquez A, Stelzl U, Lemmens I, Hirozane-Kishikawa T, Hao T, Zenkner M, Xin X, Goh KI, Yildirim MA, Simonis N, Heinzmann K, Gebreab F, Sahalie JM, Cevik S, Simon C, de Smet AS, Dann E, Smolyar A, Vinayagam A, Yu H, Szeto D, Borick H, Dricot A, Klitgord N, Murray RR, Lin C, Lalowski M, Timm J, Rau K, Boone C, Braun P, Cusick ME, Roth FP, Hill DE, Tavernier J, Wanker EE, Barabasi AL, Vidal M (2009) An empirical framework for binary interactome mapping. Nat Methods 6(1):83–90PubMedCrossRef Venkatesan K, Rual JF, Vazquez A, Stelzl U, Lemmens I, Hirozane-Kishikawa T, Hao T, Zenkner M, Xin X, Goh KI, Yildirim MA, Simonis N, Heinzmann K, Gebreab F, Sahalie JM, Cevik S, Simon C, de Smet AS, Dann E, Smolyar A, Vinayagam A, Yu H, Szeto D, Borick H, Dricot A, Klitgord N, Murray RR, Lin C, Lalowski M, Timm J, Rau K, Boone C, Braun P, Cusick ME, Roth FP, Hill DE, Tavernier J, Wanker EE, Barabasi AL, Vidal M (2009) An empirical framework for binary interactome mapping. Nat Methods 6(1):83–90PubMedCrossRef

go back to reference Thiel P, Kaiser M, Ottmann C (2012) Small-molecule stabilization of protein-protein interactions: an underestimated concept in drug discovery? Angew Chem Int Ed Engl 51(9):2012–2018PubMedCrossRef Thiel P, Kaiser M, Ottmann C (2012) Small-molecule stabilization of protein-protein interactions: an underestimated concept in drug discovery? Angew Chem Int Ed Engl 51(9):2012–2018PubMedCrossRef

go back to reference Milroy LG, Bartel M, Henen MA, Leysen S, Adriaans JM, Brunsveld L, Landrieu I, Ottmann C (2015) Stabilizer-Guided Inhibition of Protein-Protein Interactions. Angew Chem Int Ed Engl 54(52):15720–15724PubMedCrossRef Milroy LG, Bartel M, Henen MA, Leysen S, Adriaans JM, Brunsveld L, Landrieu I, Ottmann C (2015) Stabilizer-Guided Inhibition of Protein-Protein Interactions. Angew Chem Int Ed Engl 54(52):15720–15724PubMedCrossRef

go back to reference Zarzycka B, Kuenemann MA, Miteva MA, Nicolaes GA, Vriend G, Sperandio O (2016) Stabilization of protein-protein interaction complexes through small molecules. Drug Discov Today 21(1):48–57PubMedCrossRef Zarzycka B, Kuenemann MA, Miteva MA, Nicolaes GA, Vriend G, Sperandio O (2016) Stabilization of protein-protein interaction complexes through small molecules. Drug Discov Today 21(1):48–57PubMedCrossRef

go back to reference Mullard A (2012) Protein-protein interaction inhibitors get into the groove. Nat Rev Drug Discov 11(3):173–175PubMedCrossRef Mullard A (2012) Protein-protein interaction inhibitors get into the groove. Nat Rev Drug Discov 11(3):173–175PubMedCrossRef

go back to reference Whitty A, Kumaravel G (2006) Between a rock and a hard place? Nat Chem Biol 2(3):112–118PubMedCrossRef Whitty A, Kumaravel G (2006) Between a rock and a hard place? Nat Chem Biol 2(3):112–118PubMedCrossRef

go back to reference Chene P (2006) Drugs targeting protein-protein interactions. ChemMedChem 1(4):400–411PubMedCrossRef Chene P (2006) Drugs targeting protein-protein interactions. ChemMedChem 1(4):400–411PubMedCrossRef

go back to reference Fry DC (2008) Drug-like inhibitors of protein-protein interactions: a structural examination of effective protein mimicry. Curr Protein Pept Sci 9(3):240–247PubMedCrossRef Fry DC (2008) Drug-like inhibitors of protein-protein interactions: a structural examination of effective protein mimicry. Curr Protein Pept Sci 9(3):240–247PubMedCrossRef

go back to reference Cheng AC, Coleman RG, Smyth KT, Cao Q, Soulard P, Caffrey DR, Salzberg AC, Huang ES (2007) Structure-based maximal affinity model predicts small-molecule druggability. Nat Biotechnol 25(1):71–75PubMedCrossRef Cheng AC, Coleman RG, Smyth KT, Cao Q, Soulard P, Caffrey DR, Salzberg AC, Huang ES (2007) Structure-based maximal affinity model predicts small-molecule druggability. Nat Biotechnol 25(1):71–75PubMedCrossRef

go back to reference Blundell TL, Burke DF, Chirgadze D, Dhanaraj V, Hyvonen M, Innis CA, Parisini E, Pellegrini L, Sayed M, Sibanda BL (2000) Protein-protein interactions in receptor activation and intracellular signalling. Biol Chem 381(9–10):955–959PubMed Blundell TL, Burke DF, Chirgadze D, Dhanaraj V, Hyvonen M, Innis CA, Parisini E, Pellegrini L, Sayed M, Sibanda BL (2000) Protein-protein interactions in receptor activation and intracellular signalling. Biol Chem 381(9–10):955–959PubMed

go back to reference Jones S, Thornton JM (1996) Principles of protein-protein interactions. Proc Natl Acad Sci USA 93(1):13–20PubMedPubMedCentralCrossRef Jones S, Thornton JM (1996) Principles of protein-protein interactions. Proc Natl Acad Sci USA 93(1):13–20PubMedPubMedCentralCrossRef

go back to reference Lo Conte L, Chothia C, Janin J (1999) The atomic structure of protein-protein recognition sites. J Mol Biol 285(5):2177–2198PubMedCrossRef Lo Conte L, Chothia C, Janin J (1999) The atomic structure of protein-protein recognition sites. J Mol Biol 285(5):2177–2198PubMedCrossRef

go back to reference Wells JA, McClendon CL (2007) Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 450(7172):1001–1009PubMedCrossRef Wells JA, McClendon CL (2007) Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 450(7172):1001–1009PubMedCrossRef

go back to reference Buchwald P (2010) Small-molecule protein-protein interaction inhibitors: therapeutic potential in light of molecular size, chemical space, and ligand binding efficiency considerations. IUBMB Life 62(10):724–731PubMedCrossRef Buchwald P (2010) Small-molecule protein-protein interaction inhibitors: therapeutic potential in light of molecular size, chemical space, and ligand binding efficiency considerations. IUBMB Life 62(10):724–731PubMedCrossRef

go back to reference Jubb H, Higueruelo AP, Winter A, Blundell TL (2012) Structural biology and drug discovery for protein-protein interactions. Trends Pharmacol Sci 33(5):241–248PubMedCrossRef Jubb H, Higueruelo AP, Winter A, Blundell TL (2012) Structural biology and drug discovery for protein-protein interactions. Trends Pharmacol Sci 33(5):241–248PubMedCrossRef

go back to reference Moreira IS, Fernandes PA, Ramos MJ (2007) Hot spots–a review of the protein-protein interface determinant amino-acid residues. Proteins 68(4):803–812PubMedCrossRef Moreira IS, Fernandes PA, Ramos MJ (2007) Hot spots–a review of the protein-protein interface determinant amino-acid residues. Proteins 68(4):803–812PubMedCrossRef

go back to reference Smith MC, Gestwicki JE (2012) Features of protein-protein interactions that translate into potent inhibitors: topology, surface area and affinity. Expert Rev Mol Med 14:e16PubMedPubMedCentralCrossRef Smith MC, Gestwicki JE (2012) Features of protein-protein interactions that translate into potent inhibitors: topology, surface area and affinity. Expert Rev Mol Med 14:e16PubMedPubMedCentralCrossRef

go back to reference Arkin MR, Tang Y, Wells JA (2014) Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. Chem Biol 21(9):1102–1114PubMedPubMedCentralCrossRef Arkin MR, Tang Y, Wells JA (2014) Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. Chem Biol 21(9):1102–1114PubMedPubMedCentralCrossRef

go back to reference Scott DE, Bayly AR, Abell C, Skidmore J (2016) Small molecules, big targets: drug discovery faces the protein-protein interaction challenge. Nat Rev Drug Discov 15(8):533–550PubMedCrossRef Scott DE, Bayly AR, Abell C, Skidmore J (2016) Small molecules, big targets: drug discovery faces the protein-protein interaction challenge. Nat Rev Drug Discov 15(8):533–550PubMedCrossRef

go back to reference Jubb H, Blundell TL, Ascher DB (2015) Flexibility and small pockets at protein-protein interfaces: new insights into druggability. Prog Biophys Mol Biol 119(1):2–9PubMedPubMedCentralCrossRef Jubb H, Blundell TL, Ascher DB (2015) Flexibility and small pockets at protein-protein interfaces: new insights into druggability. Prog Biophys Mol Biol 119(1):2–9PubMedPubMedCentralCrossRef

go back to reference Clackson T, Wells JA (1995) A hot spot of binding energy in a hormone-receptor interface. Science 267(5196):383–386PubMedCrossRef Clackson T, Wells JA (1995) A hot spot of binding energy in a hormone-receptor interface. Science 267(5196):383–386PubMedCrossRef

go back to reference Keskin O, Gursoy A, Ma B, Nussinov R (2008) Principles of protein-protein interactions: what are the preferred ways for proteins to interact? Chem Rev 108(4):1225–1244PubMedCrossRef Keskin O, Gursoy A, Ma B, Nussinov R (2008) Principles of protein-protein interactions: what are the preferred ways for proteins to interact? Chem Rev 108(4):1225–1244PubMedCrossRef

go back to reference Bogan AA, Thorn KS (1998) Anatomy of hot spots in protein interfaces. J Mol Biol 280(1):1–9PubMedCrossRef Bogan AA, Thorn KS (1998) Anatomy of hot spots in protein interfaces. J Mol Biol 280(1):1–9PubMedCrossRef

go back to reference DeLano WL, Ultsch MH, de Vos AM, Wells JA (2000) Convergent solutions to binding at a protein-protein interface. Science 287(5456):1279–1283PubMedCrossRef DeLano WL, Ultsch MH, de Vos AM, Wells JA (2000) Convergent solutions to binding at a protein-protein interface. Science 287(5456):1279–1283PubMedCrossRef

go back to reference Atwell S, Ultsch M, De Vos AM, Wells JA (1997) Structural plasticity in a remodeled protein-protein interface. Science 278(5340):1125–1128PubMedCrossRef Atwell S, Ultsch M, De Vos AM, Wells JA (1997) Structural plasticity in a remodeled protein-protein interface. Science 278(5340):1125–1128PubMedCrossRef

go back to reference Arkin MR, Randal M, DeLano WL, Hyde J, Luong TN, Oslob JD, Raphael DR, Taylor L, Wang J, McDowell RS, Wells JA, Braisted AC (2003) Binding of small molecules to an adaptive protein-protein interface. Proc Natl Acad Sci USA 100(4):1603–1608PubMedPubMedCentralCrossRef Arkin MR, Randal M, DeLano WL, Hyde J, Luong TN, Oslob JD, Raphael DR, Taylor L, Wang J, McDowell RS, Wells JA, Braisted AC (2003) Binding of small molecules to an adaptive protein-protein interface. Proc Natl Acad Sci USA 100(4):1603–1608PubMedPubMedCentralCrossRef

go back to reference Eyrisch S, Helms V (2009) What induces pocket openings on protein surface patches involved in protein-protein interactions? J Comput Aided Mol Des 23(2):73–86PubMedCrossRef Eyrisch S, Helms V (2009) What induces pocket openings on protein surface patches involved in protein-protein interactions? J Comput Aided Mol Des 23(2):73–86PubMedCrossRef

go back to reference Bruncko M, Oost TK, Belli BA, Ding H, Joseph MK, Kunzer A, Martineau D, McClellan WJ, Mitten M, Ng SC, Nimmer PM, Oltersdorf T, Park CM, Petros AM, Shoemaker AR, Song X, Wang X, Wendt MD, Zhang H, Fesik SW, Rosenberg SH, Elmore SW (2007) Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL. J Med Chem 50(4):641–662PubMedCrossRef Bruncko M, Oost TK, Belli BA, Ding H, Joseph MK, Kunzer A, Martineau D, McClellan WJ, Mitten M, Ng SC, Nimmer PM, Oltersdorf T, Park CM, Petros AM, Shoemaker AR, Song X, Wang X, Wendt MD, Zhang H, Fesik SW, Rosenberg SH, Elmore SW (2007) Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL. J Med Chem 50(4):641–662PubMedCrossRef

go back to reference Grasberger BL, Lu T, Schubert C, Parks DJ, Carver TE, Koblish HK, Cummings MD, LaFrance LV, Milkiewicz KL, Calvo RR, Maguire D, Lattanze J, Franks CF, Zhao S, Ramachandren K, Bylebyl GR, Zhang M, Manthey CL, Petrella EC, Pantoliano MW, Deckman IC, Spurlino JC, Maroney AC, Tomczuk BE, Molloy CJ, Bone RF (2005) Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells. J Med Chem 48(4):909–912PubMedCrossRef Grasberger BL, Lu T, Schubert C, Parks DJ, Carver TE, Koblish HK, Cummings MD, LaFrance LV, Milkiewicz KL, Calvo RR, Maguire D, Lattanze J, Franks CF, Zhao S, Ramachandren K, Bylebyl GR, Zhang M, Manthey CL, Petrella EC, Pantoliano MW, Deckman IC, Spurlino JC, Maroney AC, Tomczuk BE, Molloy CJ, Bone RF (2005) Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells. J Med Chem 48(4):909–912PubMedCrossRef

go back to reference Wang Y, Coulombe R, Cameron DR, Thauvette L, Massariol MJ, Amon LM, Fink D, Titolo S, Welchner E, Yoakim C, Archambault J, White PW (2004) Crystal structure of the E2 transactivation domain of human papillomavirus type 11 bound to a protein interaction inhibitor. J Biol Chem 279(8):6976–6985PubMedCrossRef Wang Y, Coulombe R, Cameron DR, Thauvette L, Massariol MJ, Amon LM, Fink D, Titolo S, Welchner E, Yoakim C, Archambault J, White PW (2004) Crystal structure of the E2 transactivation domain of human papillomavirus type 11 bound to a protein interaction inhibitor. J Biol Chem 279(8):6976–6985PubMedCrossRef

go back to reference Cunningham BC, Wells JA (1989) High-resolution epitope mapping of hGH-receptor interactions by alanine-scanning mutagenesis. Science 244(4908):1081–1085PubMedCrossRef Cunningham BC, Wells JA (1989) High-resolution epitope mapping of hGH-receptor interactions by alanine-scanning mutagenesis. Science 244(4908):1081–1085PubMedCrossRef

go back to reference Kozakov D, Hall DR, Chuang GY, Cencic R, Brenke R, Grove LE, Beglov D, Pelletier J, Whitty A, Vajda S (2011) Structural conservation of druggable hot spots in protein-protein interfaces. Proc Natl Acad Sci USA 108(33):13528–13533PubMedPubMedCentralCrossRef Kozakov D, Hall DR, Chuang GY, Cencic R, Brenke R, Grove LE, Beglov D, Pelletier J, Whitty A, Vajda S (2011) Structural conservation of druggable hot spots in protein-protein interfaces. Proc Natl Acad Sci USA 108(33):13528–13533PubMedPubMedCentralCrossRef

go back to reference Beglov D, Hall DR, Brenke R, Shapovalov MV, Dunbrack RL Jr, Kozakov D, Vajda S (2012) Minimal ensembles of side chain conformers for modeling protein-protein interactions. Proteins 80(2):591–601PubMedCrossRef Beglov D, Hall DR, Brenke R, Shapovalov MV, Dunbrack RL Jr, Kozakov D, Vajda S (2012) Minimal ensembles of side chain conformers for modeling protein-protein interactions. Proteins 80(2):591–601PubMedCrossRef

go back to reference Yang CY, Wang S (2011) Hydrophobic binding hot spots of Bcl-xL protein-protein interfaces by cosolvent molecular dynamics simulation. ACS Med Chem Lett 2(4):280–284PubMedPubMedCentralCrossRef Yang CY, Wang S (2011) Hydrophobic binding hot spots of Bcl-xL protein-protein interfaces by cosolvent molecular dynamics simulation. ACS Med Chem Lett 2(4):280–284PubMedPubMedCentralCrossRef

go back to reference Klepeis JL, Lindorff-Larsen K, Dror RO, Shaw DE (2009) Long-timescale molecular dynamics simulations of protein structure and function. Curr Opin Struct Biol 19(2):120–127PubMedCrossRef Klepeis JL, Lindorff-Larsen K, Dror RO, Shaw DE (2009) Long-timescale molecular dynamics simulations of protein structure and function. Curr Opin Struct Biol 19(2):120–127PubMedCrossRef

go back to reference Fuller JC, Burgoyne NJ, Jackson RM (2009) Predicting druggable binding sites at the protein-protein interface. Drug Discov Today 14(3–4):155–161PubMedCrossRef Fuller JC, Burgoyne NJ, Jackson RM (2009) Predicting druggable binding sites at the protein-protein interface. Drug Discov Today 14(3–4):155–161PubMedCrossRef

go back to reference Villoutreix BO, Bastard K, Sperandio O, Fahraeus R, Poyet JL, Calvo F, Deprez B, Miteva MA (2008) In silico-in vitro screening of protein-protein interactions: towards the next generation of therapeutics. Curr Pharm Biotechnol 9(2):103–122PubMedCrossRef Villoutreix BO, Bastard K, Sperandio O, Fahraeus R, Poyet JL, Calvo F, Deprez B, Miteva MA (2008) In silico-in vitro screening of protein-protein interactions: towards the next generation of therapeutics. Curr Pharm Biotechnol 9(2):103–122PubMedCrossRef

go back to reference Zinzalla G, Thurston DE (2009) Targeting protein-protein interactions for therapeutic intervention: a challenge for the future. Future Med Chem 1(1):65–93PubMedCrossRef Zinzalla G, Thurston DE (2009) Targeting protein-protein interactions for therapeutic intervention: a challenge for the future. Future Med Chem 1(1):65–93PubMedCrossRef

go back to reference Meireles LM, Mustata G (2011) Discovery of modulators of protein-protein interactions: current approaches and limitations. Curr Top Med Chem 11(3):248–257PubMedCrossRef Meireles LM, Mustata G (2011) Discovery of modulators of protein-protein interactions: current approaches and limitations. Curr Top Med Chem 11(3):248–257PubMedCrossRef

go back to reference Jin L, Wang W, Fang G (2014) Targeting protein-protein interaction by small molecules. Annu Rev Pharmacol Toxicol 54:435–456PubMedCrossRef Jin L, Wang W, Fang G (2014) Targeting protein-protein interaction by small molecules. Annu Rev Pharmacol Toxicol 54:435–456PubMedCrossRef

go back to reference Aeluri M, Chamakuri S, Dasari B, Guduru SK, Jimmidi R, Jogula S, Arya P (2014) Small molecule modulators of protein-protein interactions: selected case studies. Chem Rev 114(9):4640–4694PubMedCrossRef Aeluri M, Chamakuri S, Dasari B, Guduru SK, Jimmidi R, Jogula S, Arya P (2014) Small molecule modulators of protein-protein interactions: selected case studies. Chem Rev 114(9):4640–4694PubMedCrossRef

go back to reference Milroy LG, Grossmann TN, Hennig S, Brunsveld L, Ottmann C (2014) Modulators of protein-protein interactions. Chem Rev 114(9):4695–4748PubMedCrossRef Milroy LG, Grossmann TN, Hennig S, Brunsveld L, Ottmann C (2014) Modulators of protein-protein interactions. Chem Rev 114(9):4695–4748PubMedCrossRef

go back to reference Higueruelo AP, Jubb H, Blundell TL (2013) Protein-protein interactions as druggable targets: recent technological advances. Curr Opin Pharmacol 13(5):791–796PubMedCrossRef Higueruelo AP, Jubb H, Blundell TL (2013) Protein-protein interactions as druggable targets: recent technological advances. Curr Opin Pharmacol 13(5):791–796PubMedCrossRef

go back to reference Villoutreix BO, Labbe CM, Lagorce D, Laconde G, Sperandio O (2012) A leap into the chemical space of protein-protein interaction inhibitors. Curr Pharm Des 18(30):4648–4667PubMedPubMedCentralCrossRef Villoutreix BO, Labbe CM, Lagorce D, Laconde G, Sperandio O (2012) A leap into the chemical space of protein-protein interaction inhibitors. Curr Pharm Des 18(30):4648–4667PubMedPubMedCentralCrossRef

go back to reference Valkov E, Sharpe T, Marsh M, Greive S, Hyvonen M (2012) Targeting protein-protein interactions and fragment-based drug discovery. Top Curr Chem 317:145–179PubMedCrossRef Valkov E, Sharpe T, Marsh M, Greive S, Hyvonen M (2012) Targeting protein-protein interactions and fragment-based drug discovery. Top Curr Chem 317:145–179PubMedCrossRef

go back to reference Azzarito V, Long K, Murphy NS, Wilson AJ (2013) Inhibition of alpha-helix-mediated protein-protein interactions using designed molecules. Nat Chem 5(3):161–173PubMedCrossRef Azzarito V, Long K, Murphy NS, Wilson AJ (2013) Inhibition of alpha-helix-mediated protein-protein interactions using designed molecules. Nat Chem 5(3):161–173PubMedCrossRef

go back to reference London N, Raveh B, Schueler-Furman O (2013) Druggable protein-protein interactions–from hot spots to hot segments. Curr Opin Chem Biol 17(6):952–959PubMedCrossRef London N, Raveh B, Schueler-Furman O (2013) Druggable protein-protein interactions–from hot spots to hot segments. Curr Opin Chem Biol 17(6):952–959PubMedCrossRef

go back to reference Ivanov AA, Khuri FR, Fu H (2013) Targeting protein-protein interactions as an anticancer strategy. Trends Pharmacol Sci 34(7):393–400PubMedPubMedCentralCrossRef Ivanov AA, Khuri FR, Fu H (2013) Targeting protein-protein interactions as an anticancer strategy. Trends Pharmacol Sci 34(7):393–400PubMedPubMedCentralCrossRef

go back to reference Nero TL, Morton CJ, Holien JK, Wielens J, Parker MW (2014) Oncogenic protein interfaces: small molecules, big challenges. Nat Rev Cancer 14(4):248–262PubMedCrossRef Nero TL, Morton CJ, Holien JK, Wielens J, Parker MW (2014) Oncogenic protein interfaces: small molecules, big challenges. Nat Rev Cancer 14(4):248–262PubMedCrossRef

go back to reference Sheng C, Dong G, Miao Z, Zhang W, Wang W (2015) State-of-the-art strategies for targeting protein-protein interactions by small-molecule inhibitors. Chem Soc Rev 44(22):8238–8259PubMedCrossRef Sheng C, Dong G, Miao Z, Zhang W, Wang W (2015) State-of-the-art strategies for targeting protein-protein interactions by small-molecule inhibitors. Chem Soc Rev 44(22):8238–8259PubMedCrossRef

go back to reference Guo W, Wisniewski JA, Ji H (2014) Hot spot-based design of small-molecule inhibitors for protein-protein interactions. Bioorg Med Chem Lett 24(11):2546–2554PubMedCrossRef Guo W, Wisniewski JA, Ji H (2014) Hot spot-based design of small-molecule inhibitors for protein-protein interactions. Bioorg Med Chem Lett 24(11):2546–2554PubMedCrossRef

go back to reference Wanner J, Fry DC, Peng Z, Roberts J (2011) Druggability assessment of protein-protein interfaces. Future Med Chem 3(16):2021–2038PubMedCrossRef Wanner J, Fry DC, Peng Z, Roberts J (2011) Druggability assessment of protein-protein interfaces. Future Med Chem 3(16):2021–2038PubMedCrossRef

go back to reference Eyrisch S, Helms V (2007) Transient pockets on protein surfaces involved in protein-protein interaction. J Med Chem 50(15):3457–3464PubMedCrossRef Eyrisch S, Helms V (2007) Transient pockets on protein surfaces involved in protein-protein interaction. J Med Chem 50(15):3457–3464PubMedCrossRef

go back to reference Villoutreix BO, Kuenemann MA, Poyet JL, Bruzzoni-Giovanelli H, Labbe C, Lagorce D, Sperandio O, Miteva MA (2014) Drug-Like protein-protein interaction modulators: challenges and opportunities for drug discovery and chemical biology. Mol Inform 33(6–7):414–437PubMedPubMedCentralCrossRef Villoutreix BO, Kuenemann MA, Poyet JL, Bruzzoni-Giovanelli H, Labbe C, Lagorce D, Sperandio O, Miteva MA (2014) Drug-Like protein-protein interaction modulators: challenges and opportunities for drug discovery and chemical biology. Mol Inform 33(6–7):414–437PubMedPubMedCentralCrossRef

go back to reference Berg T (2008) Small-molecule inhibitors of protein-protein interactions. Curr Opin Drug Discov Devel 11(5):666–674PubMed Berg T (2008) Small-molecule inhibitors of protein-protein interactions. Curr Opin Drug Discov Devel 11(5):666–674PubMed

go back to reference Ashkenazi A, Fairbrother WJ, Leverson JD, Souers AJ (2017) From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov 16(4):273–284PubMedCrossRef Ashkenazi A, Fairbrother WJ, Leverson JD, Souers AJ (2017) From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors. Nat Rev Drug Discov 16(4):273–284PubMedCrossRef

go back to reference Zhong M, Hanan EJ, Shen W, Bui M, Arkin MR, Barr KJ, Evanchik MJ, Hoch U, Hyde J, Martell JR, Oslob JD, Paulvannan K, Prabhu S, Silverman JA, Wright J, Yu CH, Zhu J, Flanagan WM (2011) Structure-activity relationship (SAR) of the alpha-amino acid residue of potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists. Bioorg Med Chem Lett 21(1):307–310PubMedCrossRef Zhong M, Hanan EJ, Shen W, Bui M, Arkin MR, Barr KJ, Evanchik MJ, Hoch U, Hyde J, Martell JR, Oslob JD, Paulvannan K, Prabhu S, Silverman JA, Wright J, Yu CH, Zhu J, Flanagan WM (2011) Structure-activity relationship (SAR) of the alpha-amino acid residue of potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists. Bioorg Med Chem Lett 21(1):307–310PubMedCrossRef

go back to reference Cervantes-Gomez F, Lamothe B, Woyach JA, Wierda WG, Keating MJ, Balakrishnan K, Gandhi V (2015) Pharmacological and protein profiling suggests venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia. Clin Cancer Res 21(16):3705–3715PubMedPubMedCentralCrossRef Cervantes-Gomez F, Lamothe B, Woyach JA, Wierda WG, Keating MJ, Balakrishnan K, Gandhi V (2015) Pharmacological and protein profiling suggests venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia. Clin Cancer Res 21(16):3705–3715PubMedPubMedCentralCrossRef

go back to reference Konopleva M, Watt J, Contractor R, Tsao T, Harris D, Estrov Z, Bornmann W, Kantarjian H, Viallet J, Samudio I, Andreeff M (2008) Mechanisms of antileukemic activity of the novel Bcl-2 homology domain-3 mimetic GX15-070 (obatoclax). Cancer Res 68(9):3413–3420PubMedPubMedCentralCrossRef Konopleva M, Watt J, Contractor R, Tsao T, Harris D, Estrov Z, Bornmann W, Kantarjian H, Viallet J, Samudio I, Andreeff M (2008) Mechanisms of antileukemic activity of the novel Bcl-2 homology domain-3 mimetic GX15-070 (obatoclax). Cancer Res 68(9):3413–3420PubMedPubMedCentralCrossRef

go back to reference Ding Q, Zhang Z, Liu JJ, Jiang N, Zhang J, Ross TM, Chu XJ, Bartkovitz D, Podlaski F, Janson C, Tovar C, Filipovic ZM, Higgins B, Glenn K, Packman K, Vassilev LT, Graves B (2013) Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J Med Chem 56(14):5979–5983PubMedCrossRef Ding Q, Zhang Z, Liu JJ, Jiang N, Zhang J, Ross TM, Chu XJ, Bartkovitz D, Podlaski F, Janson C, Tovar C, Filipovic ZM, Higgins B, Glenn K, Packman K, Vassilev LT, Graves B (2013) Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J Med Chem 56(14):5979–5983PubMedCrossRef

go back to reference Sun D, Li Z, Rew Y, Gribble M, Bartberger MD, Beck HP, Canon J, Chen A, Chen X, Chow D, Deignan J, Duquette J, Eksterowicz J, Fisher B, Fox BM, Fu J, Gonzalez AZ, Gonzalez-Lopez De Turiso F, Houze JB, Huang X, Jiang M, Jin L, Kayser F, Liu JJ, Lo MC, Long AM, Lucas B, McGee LR, McIntosh J, Mihalic J, Oliner JD, Osgood T, Peterson ML, Roveto P, Saiki AY, Shaffer P, Toteva M, Wang Y, Wang YC, Wortman S, Yakowec P, Yan X, Ye Q, Yu D, Yu M, Zhao X, Zhou J, Zhu J, Olson SH, Medina JC (2014) Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development. J Med Chem 57(4):1454–1472PubMedCrossRef Sun D, Li Z, Rew Y, Gribble M, Bartberger MD, Beck HP, Canon J, Chen A, Chen X, Chow D, Deignan J, Duquette J, Eksterowicz J, Fisher B, Fox BM, Fu J, Gonzalez AZ, Gonzalez-Lopez De Turiso F, Houze JB, Huang X, Jiang M, Jin L, Kayser F, Liu JJ, Lo MC, Long AM, Lucas B, McGee LR, McIntosh J, Mihalic J, Oliner JD, Osgood T, Peterson ML, Roveto P, Saiki AY, Shaffer P, Toteva M, Wang Y, Wang YC, Wortman S, Yakowec P, Yan X, Ye Q, Yu D, Yu M, Zhao X, Zhou J, Zhu J, Olson SH, Medina JC (2014) Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development. J Med Chem 57(4):1454–1472PubMedCrossRef

go back to reference Jeay S, Gaulis S, Ferretti S, Bitter H, Ito M, Valat T, Murakami M, Ruetz S, Guthy DA, Rynn C, Jensen MR, Wiesmann M, Kallen J, Furet P, Gessier F, Holzer P, Masuya K, Wurthner J, Halilovic E, Hofmann F, Sellers WR, Graus Porta D (2015) A distinct p 53 target gene set predicts for response to the selective p53-HDM2 inhibitor NVP-CGM097. eLife e06498 Jeay S, Gaulis S, Ferretti S, Bitter H, Ito M, Valat T, Murakami M, Ruetz S, Guthy DA, Rynn C, Jensen MR, Wiesmann M, Kallen J, Furet P, Gessier F, Holzer P, Masuya K, Wurthner J, Halilovic E, Hofmann F, Sellers WR, Graus Porta D (2015) A distinct p 53 target gene set predicts for response to the selective p53-HDM2 inhibitor NVP-CGM097. eLife e06498

go back to reference Perez VL, Pflugfelder SC, Zhang S, Shojaei A, Haque R (2016) Lifitegrast, a novel integrin antagonist for treatment of dry eye disease. Ocul Surf 14(2):207–215PubMedCrossRef Perez VL, Pflugfelder SC, Zhang S, Shojaei A, Haque R (2016) Lifitegrast, a novel integrin antagonist for treatment of dry eye disease. Ocul Surf 14(2):207–215PubMedCrossRef

go back to reference Tabernero J, Dirix L, Schoffski P, Cervantes A, Lopez-Martin JA, Capdevila J, van Beijsterveldt L, Platero S, Hall B, Yuan Z, Knoblauch R, Zhuang SH (2011) A phase I first-in-human pharmacokinetic and pharmacodynamic study of serdemetan in patients with advanced solid tumors. Clin Cancer Res 17(19):6313–6321PubMedCrossRef Tabernero J, Dirix L, Schoffski P, Cervantes A, Lopez-Martin JA, Capdevila J, van Beijsterveldt L, Platero S, Hall B, Yuan Z, Knoblauch R, Zhuang SH (2011) A phase I first-in-human pharmacokinetic and pharmacodynamic study of serdemetan in patients with advanced solid tumors. Clin Cancer Res 17(19):6313–6321PubMedCrossRef

go back to reference Vu B, Wovkulich P, Pizzolato G, Lovey A, Ding Q, Jiang N, Liu JJ, Zhao C, Glenn K, Wen Y, Tovar C, Packman K, Vassilev L, Graves B (2013) Discovery of RG7112: a small-molecule MDM2 inhibitor in clinical development. ACS Med Chem Lett 4(5):466–469PubMedPubMedCentralCrossRef Vu B, Wovkulich P, Pizzolato G, Lovey A, Ding Q, Jiang N, Liu JJ, Zhao C, Glenn K, Wen Y, Tovar C, Packman K, Vassilev L, Graves B (2013) Discovery of RG7112: a small-molecule MDM2 inhibitor in clinical development. ACS Med Chem Lett 4(5):466–469PubMedPubMedCentralCrossRef

go back to reference Tovar C, Graves B, Packman K, Filipovic Z, Higgins B, Xia M, Tardell C, Garrido R, Lee E, Kolinsky K, To KH, Linn M, Podlaski F, Wovkulich P, Vu B, Vassilev LT (2013) MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models. Cancer Res 73(8):2587–2597PubMedCrossRef Tovar C, Graves B, Packman K, Filipovic Z, Higgins B, Xia M, Tardell C, Garrido R, Lee E, Kolinsky K, To KH, Linn M, Podlaski F, Wovkulich P, Vu B, Vassilev LT (2013) MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models. Cancer Res 73(8):2587–2597PubMedCrossRef

go back to reference Wang S, Sun W, Zhao Y, McEachern D, Meaux I, Barriere C, Stuckey JA, Meagher JL, Bai L, Liu L, Hoffman-Luca CG, Lu J, Shangary S, Yu S, Bernard D, Aguilar A, Dos-Santos O, Besret L, Guerif S, Pannier P, Gorge-Bernat D, Debussche L (2014) SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression. Cancer Res 74(20):5855–5865PubMedPubMedCentralCrossRef Wang S, Sun W, Zhao Y, McEachern D, Meaux I, Barriere C, Stuckey JA, Meagher JL, Bai L, Liu L, Hoffman-Luca CG, Lu J, Shangary S, Yu S, Bernard D, Aguilar A, Dos-Santos O, Besret L, Guerif S, Pannier P, Gorge-Bernat D, Debussche L (2014) SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression. Cancer Res 74(20):5855–5865PubMedPubMedCentralCrossRef

go back to reference Potin D, Launay M, Monatlik F, Malabre P, Fabreguettes M, Fouquet A, Maillet M, Nicolai E, Dorgeret L, Chevallier F, Besse D, Dufort M, Caussade F, Ahmad SZ, Stetsko DK, Skala S, Davis PM, Balimane P, Patel K, Yang Z, Marathe P, Postelneck J, Townsend RM, Goldfarb V, Sheriff S, Einspahr H, Kish K, Malley MF, DiMarco JD, Gougoutas JZ, Kadiyala P, Cheney DL, Tejwani RW, Murphy DK, McIntyre KW, Yang X, Chao S, Leith L, Xiao Z, Mathur A, Chen BC, Wu DR, Traeger SC, McKinnon M, Barrish JC, Robl JA, Iwanowicz EJ, Suchard SJ, Dhar TG (2006) Discovery and development of 5-[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl-methyl]-3-thiophenecarboxylic acid (BMS-587101)—a small molecule antagonist of leukocyte function associated antigen-1. J Med Chem 49(24):6946–6949PubMedCrossRef Potin D, Launay M, Monatlik F, Malabre P, Fabreguettes M, Fouquet A, Maillet M, Nicolai E, Dorgeret L, Chevallier F, Besse D, Dufort M, Caussade F, Ahmad SZ, Stetsko DK, Skala S, Davis PM, Balimane P, Patel K, Yang Z, Marathe P, Postelneck J, Townsend RM, Goldfarb V, Sheriff S, Einspahr H, Kish K, Malley MF, DiMarco JD, Gougoutas JZ, Kadiyala P, Cheney DL, Tejwani RW, Murphy DK, McIntyre KW, Yang X, Chao S, Leith L, Xiao Z, Mathur A, Chen BC, Wu DR, Traeger SC, McKinnon M, Barrish JC, Robl JA, Iwanowicz EJ, Suchard SJ, Dhar TG (2006) Discovery and development of 5-[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl-methyl]-3-thiophenecarboxylic acid (BMS-587101)—a small molecule antagonist of leukocyte function associated antigen-1. J Med Chem 49(24):6946–6949PubMedCrossRef

go back to reference Watterson SH, Xiao Z, Dodd DS, Tortolani DR, Vaccaro W, Potin D, Launay M, Stetsko DK, Skala S, Davis PM, Lee D, Yang X, McIntyre KW, Balimane P, Patel K, Yang Z, Marathe P, Kadiyala P, Tebben AJ, Sheriff S, Chang CY, Ziemba T, Zhang H, Chen BC, DelMonte AJ, Aranibar N, McKinnon M, Barrish JC, Suchard SJ, Murali Dhar TG (2010) Small molecule antagonist of leukocyte function associated antigen-1 (LFA-1): structure-activity relationships leading to the identification of 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-tria zaspiro[4.4]nonan-7-yl)nicotinic acid (BMS-688521). J Med Chem 53(9):3814–3830PubMedCrossRef Watterson SH, Xiao Z, Dodd DS, Tortolani DR, Vaccaro W, Potin D, Launay M, Stetsko DK, Skala S, Davis PM, Lee D, Yang X, McIntyre KW, Balimane P, Patel K, Yang Z, Marathe P, Kadiyala P, Tebben AJ, Sheriff S, Chang CY, Ziemba T, Zhang H, Chen BC, DelMonte AJ, Aranibar N, McKinnon M, Barrish JC, Suchard SJ, Murali Dhar TG (2010) Small molecule antagonist of leukocyte function associated antigen-1 (LFA-1): structure-activity relationships leading to the identification of 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-tria zaspiro[4.4]nonan-7-yl)nicotinic acid (BMS-688521). J Med Chem 53(9):3814–3830PubMedCrossRef

go back to reference Kelly TA, Kim JML, R.M. (2004) Preparation of [6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonylamino]propionamide derivatives for treatment of inflammatory disease. WO 2004041827 Kelly TA, Kim JML, R.M. (2004) Preparation of [6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonylamino]propionamide derivatives for treatment of inflammatory disease. WO 2004041827

go back to reference Polishchuk PG, Samoylenko GV, Khristova TM, Krysko OL, Kabanova TA, Kabanov VM, Kornylov AY, Klimchuk O, Langer T, Andronati SA, Kuz’min VE, Krysko AA, Varnek A (2015) Design, virtual screening, and synthesis of antagonists of alphaIIbbeta3 as antiplatelet agents. J Med Chem 58(19):7681–7694PubMedCrossRef Polishchuk PG, Samoylenko GV, Khristova TM, Krysko OL, Kabanova TA, Kabanov VM, Kornylov AY, Klimchuk O, Langer T, Andronati SA, Kuz’min VE, Krysko AA, Varnek A (2015) Design, virtual screening, and synthesis of antagonists of alphaIIbbeta3 as antiplatelet agents. J Med Chem 58(19):7681–7694PubMedCrossRef

go back to reference Gowda RM, Khan IA, Vasavada BC, Sacchi TJ (2004) Therapeutics of platelet glycoprotein IIb/IIIa receptor antagonism. Am J Ther 11(4):302–307PubMedCrossRef Gowda RM, Khan IA, Vasavada BC, Sacchi TJ (2004) Therapeutics of platelet glycoprotein IIb/IIIa receptor antagonism. Am J Ther 11(4):302–307PubMedCrossRef

go back to reference Zablocki JA, Rico JG, Garland RB, Rogers TE, Williams K, Schretzman LA, Rao SA, Bovy PR, Tjoeng FS, Lindmark RJ et al (1995) Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp sequence of fibrinogen. (Aminobenzamidino)succinyl (ABAS) series of orally active fibrinogen receptor antagonists. J Med Chem 38(13):2378–2394PubMedCrossRef Zablocki JA, Rico JG, Garland RB, Rogers TE, Williams K, Schretzman LA, Rao SA, Bovy PR, Tjoeng FS, Lindmark RJ et al (1995) Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp sequence of fibrinogen. (Aminobenzamidino)succinyl (ABAS) series of orally active fibrinogen receptor antagonists. J Med Chem 38(13):2378–2394PubMedCrossRef

go back to reference Feldstein CA (1999) Sibrafiban (Genentech). IDrugs 2(5):460–465PubMed Feldstein CA (1999) Sibrafiban (Genentech). IDrugs 2(5):460–465PubMed

go back to reference Sugiura T, Kageyama S, Andou A, Miyazawa T, Ejima C, Nakayama A, Dohi T, Eda H (2013) Oral treatment with a novel small molecule alpha 4 integrin antagonist, AJM300, prevents the development of experimental colitis in mice. J Crohns Colitis 7(11):e533–e542PubMedCrossRef Sugiura T, Kageyama S, Andou A, Miyazawa T, Ejima C, Nakayama A, Dohi T, Eda H (2013) Oral treatment with a novel small molecule alpha 4 integrin antagonist, AJM300, prevents the development of experimental colitis in mice. J Crohns Colitis 7(11):e533–e542PubMedCrossRef

go back to reference Halland N, Blum H, Buning C, Kohlmann M, Lindenschmidt A (2014) Small macrocycles as highly active integrin alpha2beta1 antagonists. ACS Med Chem Lett 5(2):193–198PubMedPubMedCentralCrossRef Halland N, Blum H, Buning C, Kohlmann M, Lindenschmidt A (2014) Small macrocycles as highly active integrin alpha2beta1 antagonists. ACS Med Chem Lett 5(2):193–198PubMedPubMedCentralCrossRef

go back to reference Davenport RJ, Munday JR (2007) Alpha4-integrin antagonism—an effective approach for the treatment of inflammatory diseases? Drug Discov Today 12(13–14):569–576PubMedCrossRef Davenport RJ, Munday JR (2007) Alpha4-integrin antagonism—an effective approach for the treatment of inflammatory diseases? Drug Discov Today 12(13–14):569–576PubMedCrossRef

go back to reference Astles PC, Harris NV, Morley AD (1999) Preparation of substituted β-alanines as integrin-mediated cell adhesion inhibitors. WO 9933789 Astles PC, Harris NV, Morley AD (1999) Preparation of substituted β-alanines as integrin-mediated cell adhesion inhibitors. WO 9933789

go back to reference Sircar I, Gudmundsson KS, Martin R, Liang J, Nomura S, Jayakumar H, Teegarden BR, Nowlin DM, Cardarelli PM, Mah JR, Connell S, Griffith RC, Lazarides E (2002) Synthesis and SAR of N-benzoyl-L-biphenylalanine derivatives: discovery of TR-14035, a dual alpha(4)beta(7)/alpha(4)beta(1) integrin antagonist. Bioorg Med Chem 10(6):2051–2066PubMedCrossRef Sircar I, Gudmundsson KS, Martin R, Liang J, Nomura S, Jayakumar H, Teegarden BR, Nowlin DM, Cardarelli PM, Mah JR, Connell S, Griffith RC, Lazarides E (2002) Synthesis and SAR of N-benzoyl-L-biphenylalanine derivatives: discovery of TR-14035, a dual alpha(4)beta(7)/alpha(4)beta(1) integrin antagonist. Bioorg Med Chem 10(6):2051–2066PubMedCrossRef

go back to reference Cai J, Hu Y, Li W, Li L, Li S, Zhang M, Li Q (2011) The neuroprotective effect of propofol against brain ischemia mediated by the glutamatergic signaling pathway in rats. Neurochem Res 36(10):1724–1731PubMedCrossRef Cai J, Hu Y, Li W, Li L, Li S, Zhang M, Li Q (2011) The neuroprotective effect of propofol against brain ischemia mediated by the glutamatergic signaling pathway in rats. Neurochem Res 36(10):1724–1731PubMedCrossRef

go back to reference Derakhshan A, Chen Z, Van Waes C (2017) Therapeutic small molecules target inhibitor of apoptosis proteins in cancers with deregulation of extrinsic and intrinsic cell death pathways. Clin Cancer Res 23(6):1379–1387PubMedCrossRef Derakhshan A, Chen Z, Van Waes C (2017) Therapeutic small molecules target inhibitor of apoptosis proteins in cancers with deregulation of extrinsic and intrinsic cell death pathways. Clin Cancer Res 23(6):1379–1387PubMedCrossRef

go back to reference Benetatos CA, Mitsuuchi Y, Burns JM, Neiman EM, Condon SM, Yu G, Seipel ME, Kapoor GS, Laporte MG, Rippin SR, Deng Y, Hendi MS, Tirunahari PK, Lee YH, Haimowitz T, Alexander MD, Graham MA, Weng D, Shi Y, McKinlay MA, Chunduru SK (2014) Birinapant (TL32711), a bivalent SMAC mimetic, targets TRAF2-associated cIAPs, abrogates TNF-induced NF-kappaB activation, and is active in patient-derived xenograft models. Mol Cancer Ther 13(4):867–879PubMedCrossRef Benetatos CA, Mitsuuchi Y, Burns JM, Neiman EM, Condon SM, Yu G, Seipel ME, Kapoor GS, Laporte MG, Rippin SR, Deng Y, Hendi MS, Tirunahari PK, Lee YH, Haimowitz T, Alexander MD, Graham MA, Weng D, Shi Y, McKinlay MA, Chunduru SK (2014) Birinapant (TL32711), a bivalent SMAC mimetic, targets TRAF2-associated cIAPs, abrogates TNF-induced NF-kappaB activation, and is active in patient-derived xenograft models. Mol Cancer Ther 13(4):867–879PubMedCrossRef

go back to reference Wong H, Gould SE, Budha N, Darbonne WC, Kadel EE 3rd, La H, Alicke B, Halladay JS, Erickson R, Portera C, Tolcher AW, Infante JR, Mamounas M, Flygare JA, Hop CE, Fairbrother WJ (2013) Learning and confirming with preclinical studies: modeling and simulation in the discovery of GDC-0917, an inhibitor of apoptosis proteins antagonist. Drug Metab Dispos 41(12):2104–2113PubMedCrossRef Wong H, Gould SE, Budha N, Darbonne WC, Kadel EE 3rd, La H, Alicke B, Halladay JS, Erickson R, Portera C, Tolcher AW, Infante JR, Mamounas M, Flygare JA, Hop CE, Fairbrother WJ (2013) Learning and confirming with preclinical studies: modeling and simulation in the discovery of GDC-0917, an inhibitor of apoptosis proteins antagonist. Drug Metab Dispos 41(12):2104–2113PubMedCrossRef

go back to reference Flygare JA, Beresini M, Budha N, Chan H, Chan IT, Cheeti S, Cohen F, Deshayes K, Doerner K, Eckhardt SG, Elliott LO, Feng B, Franklin MC, Reisner SF, Gazzard L, Halladay J, Hymowitz SG, La H, LoRusso P, Maurer B, Murray L, Plise E, Quan C, Stephan JP, Young SG, Tom J, Tsui V, Um J, Varfolomeev E, Vucic D, Wagner AJ, Wallweber HJ, Wang L, Ware J, Wen Z, Wong H, Wong JM, Wong M, Wong S, Yu R, Zobel K, Fairbrother WJ (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(9):4101–4113PubMedPubMedCentralCrossRef Flygare JA, Beresini M, Budha N, Chan H, Chan IT, Cheeti S, Cohen F, Deshayes K, Doerner K, Eckhardt SG, Elliott LO, Feng B, Franklin MC, Reisner SF, Gazzard L, Halladay J, Hymowitz SG, La H, LoRusso P, Maurer B, Murray L, Plise E, Quan C, Stephan JP, Young SG, Tom J, Tsui V, Um J, Varfolomeev E, Vucic D, Wagner AJ, Wallweber HJ, Wang L, Ware J, Wen Z, Wong H, Wong JM, Wong M, Wong S, Yu R, Zobel K, Fairbrother WJ (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(9):4101–4113PubMedPubMedCentralCrossRef

go back to reference Bailey D, Jahagirdar R, Gordon A, Hafiane A, Campbell S, Chatur S, Wagner GS, Hansen HC, Chiacchia FS, Johansson J, Krimbou L, Wong NC, Genest J (2010) RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. J Am Coll Cardiol 55(23):2580–2589PubMedCrossRef Bailey D, Jahagirdar R, Gordon A, Hafiane A, Campbell S, Chatur S, Wagner GS, Hansen HC, Chiacchia FS, Johansson J, Krimbou L, Wong NC, Genest J (2010) RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. J Am Coll Cardiol 55(23):2580–2589PubMedCrossRef

go back to reference Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S, Chung CW, Chandwani R, Marazzi I, Wilson P, Coste H, White J, Kirilovsky J, Rice CM, Lora JM, Prinjha RK, Lee K, Tarakhovsky A (2010) Suppression of inflammation by a synthetic histone mimic. Nature 468(7327):1119–1123PubMedPubMedCentralCrossRef Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S, Chung CW, Chandwani R, Marazzi I, Wilson P, Coste H, White J, Kirilovsky J, Rice CM, Lora JM, Prinjha RK, Lee K, Tarakhovsky A (2010) Suppression of inflammation by a synthetic histone mimic. Nature 468(7327):1119–1123PubMedPubMedCentralCrossRef

go back to reference Albrecht BK, Gehling VS, Hewitt MC, Vaswani RG, Cote A, Leblanc Y, Nasveschuk CG, Bellon S, Bergeron L, Campbell R, Cantone N, Cooper MR, Cummings RT, Jayaram H, Joshi S, Mertz JA, Neiss A, Normant E, O’Meara M, Pardo E, Poy F, Sandy P, Supko J, Sims RJ 3rd, Harmange JC, Taylor AM, Audia JE (2016) Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) family as a candidate for human clinical trials. J Med Chem 59(4):1330–1339PubMedCrossRef Albrecht BK, Gehling VS, Hewitt MC, Vaswani RG, Cote A, Leblanc Y, Nasveschuk CG, Bellon S, Bergeron L, Campbell R, Cantone N, Cooper MR, Cummings RT, Jayaram H, Joshi S, Mertz JA, Neiss A, Normant E, O’Meara M, Pardo E, Poy F, Sandy P, Supko J, Sims RJ 3rd, Harmange JC, Taylor AM, Audia JE (2016) Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) family as a candidate for human clinical trials. J Med Chem 59(4):1330–1339PubMedCrossRef

go back to reference Boi M, Gaudio E, Bonetti P, Kwee I, Bernasconi E, Tarantelli C, Rinaldi A, Testoni M, Cascione L, Ponzoni M, Mensah AA, Stathis A, Stussi G, Riveiro ME, Herait P, Inghirami G, Cvitkovic E, Zucca E, Bertoni F (2015) The BET Bromodomain Inhibitor OTX015 affects pathogenetic pathways in preclinical B-cell tumor models and synergizes with targeted drugs. Clin Cancer Res 21(7):1628–1638PubMedCrossRef Boi M, Gaudio E, Bonetti P, Kwee I, Bernasconi E, Tarantelli C, Rinaldi A, Testoni M, Cascione L, Ponzoni M, Mensah AA, Stathis A, Stussi G, Riveiro ME, Herait P, Inghirami G, Cvitkovic E, Zucca E, Bertoni F (2015) The BET Bromodomain Inhibitor OTX015 affects pathogenetic pathways in preclinical B-cell tumor models and synergizes with targeted drugs. Clin Cancer Res 21(7):1628–1638PubMedCrossRef

go back to reference Schenk RL, Strasser A, Dewson G (2017) BCL-2: long and winding path from discovery to therapeutic target. Biochem Biophys Res Commun 482(3):459–469PubMedCrossRef Schenk RL, Strasser A, Dewson G (2017) BCL-2: long and winding path from discovery to therapeutic target. Biochem Biophys Res Commun 482(3):459–469PubMedCrossRef

go back to reference Adams JM, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281(5381):1322–1326PubMedCrossRef Adams JM, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281(5381):1322–1326PubMedCrossRef

go back to reference Rudin CM, Hann CL, Garon EB, Ribeiro de Oliveira M, Bonomi PD, Camidge DR, Chu Q, Giaccone G, Khaira D, Ramalingam SS, Ranson MR, Dive C, McKeegan EM, Chyla BJ, Dowell BL, Chakravartty A, Nolan CE, Rudersdorf N, Busman TA, Mabry MH, Krivoshik AP, Humerickhouse RA, Shapiro GI, Gandhi L (2012) Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res 18(11):3163–3169PubMedPubMedCentralCrossRef Rudin CM, Hann CL, Garon EB, Ribeiro de Oliveira M, Bonomi PD, Camidge DR, Chu Q, Giaccone G, Khaira D, Ramalingam SS, Ranson MR, Dive C, McKeegan EM, Chyla BJ, Dowell BL, Chakravartty A, Nolan CE, Rudersdorf N, Busman TA, Mabry MH, Krivoshik AP, Humerickhouse RA, Shapiro GI, Gandhi L (2012) Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res 18(11):3163–3169PubMedPubMedCentralCrossRef

go back to reference 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(5302):983–986PubMedCrossRef 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(5302):983–986PubMedCrossRef

go back to reference Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O’Connor JM, Oleksijew A, Petros 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 tumours. Nature 435(7042):677–681PubMedCrossRef Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O’Connor JM, Oleksijew A, Petros 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 tumours. Nature 435(7042):677–681PubMedCrossRef

go back to reference Petros AM, Dinges J, Augeri DJ, Baumeister SA, Betebenner DA, Bures MG, Elmore SW, Hajduk PJ, Joseph MK, Landis SK, Nettesheim DG, Rosenberg SH, Shen W, Thomas S, Wang X, Zanze I, Zhang H, Fesik SW (2006) Discovery of a potent inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel synthesis. J Med Chem 49(2):656–663PubMedCrossRef Petros AM, Dinges J, Augeri DJ, Baumeister SA, Betebenner DA, Bures MG, Elmore SW, Hajduk PJ, Joseph MK, Landis SK, Nettesheim DG, Rosenberg SH, Shen W, Thomas S, Wang X, Zanze I, Zhang H, Fesik SW (2006) Discovery of a potent inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel synthesis. J Med Chem 49(2):656–663PubMedCrossRef

go back to reference Wendt MD, Shen W, Kunzer A, McClellan WJ, Bruncko M, Oost TK, Ding H, Joseph MK, Zhang H, Nimmer PM, Ng SC, Shoemaker AR, Petros AM, Oleksijew A, Marsh K, Bauch J, Oltersdorf T, Belli BA, Martineau D, Fesik SW, Rosenberg SH, Elmore SW (2006) 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 49(3):1165–1181PubMedCrossRef Wendt MD, Shen W, Kunzer A, McClellan WJ, Bruncko M, Oost TK, Ding H, Joseph MK, Zhang H, Nimmer PM, Ng SC, Shoemaker AR, Petros AM, Oleksijew A, Marsh K, Bauch J, Oltersdorf T, Belli BA, Martineau D, Fesik SW, Rosenberg SH, Elmore SW (2006) 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 49(3):1165–1181PubMedCrossRef

go back to reference Park CM, Oie T, Petros AM, Zhang H, Nimmer PM, Henry RF, Elmore SW (2006) Design, synthesis, and computational studies of inhibitors of Bcl-XL. J Am Chem Soc 128(50):16206–16212PubMedCrossRef Park CM, Oie T, Petros AM, Zhang H, Nimmer PM, Henry RF, Elmore SW (2006) Design, synthesis, and computational studies of inhibitors of Bcl-XL. J Am Chem Soc 128(50):16206–16212PubMedCrossRef

go back to reference Park CM, Bruncko M, Adickes J, Bauch J, Ding H, Kunzer A, Marsh KC, Nimmer P, Shoemaker AR, Song X, Tahir SK, Tse C, Wang X, Wendt MD, Yang X, Zhang H, Fesik SW, Rosenberg SH, Elmore SW (2008) Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins. J Med Chem 51(21):6902–6915PubMedCrossRef Park CM, Bruncko M, Adickes J, Bauch J, Ding H, Kunzer A, Marsh KC, Nimmer P, Shoemaker AR, Song X, Tahir SK, Tse C, Wang X, Wendt MD, Yang X, Zhang H, Fesik SW, Rosenberg SH, Elmore SW (2008) Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins. J Med Chem 51(21):6902–6915PubMedCrossRef

go back to reference Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, Johnson EF, Marsh KC, Mitten MJ, Nimmer P, Roberts L, Tahir SK, Xiao Y, Yang X, Zhang H, Fesik S, Rosenberg SH, Elmore SW (2008) ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 68(9):3421–3428PubMedCrossRef Tse C, Shoemaker AR, Adickes J, Anderson MG, Chen J, Jin S, Johnson EF, Marsh KC, Mitten MJ, Nimmer P, Roberts L, Tahir SK, Xiao Y, Yang X, Zhang H, Fesik S, Rosenberg SH, Elmore SW (2008) ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 68(9):3421–3428PubMedCrossRef

go back to reference Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DC, Hymowitz SG, Jin S, Khaw SL, Kovar PJ, Lam LT, Lee J, Maecker HL, Marsh KC, Mason KD, Mitten MJ, Nimmer PM, Oleksijew A, Park CH, Park CM, Phillips DC, Roberts AW, Sampath D, Seymour JF, Smith ML, Sullivan GM, Tahir SK, Tse C, Wendt MD, Xiao Y, Xue JC, Zhang H, Humerickhouse RA, Rosenberg SH, Elmore SW (2013) ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 19(2):202–208PubMedCrossRef Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DC, Hymowitz SG, Jin S, Khaw SL, Kovar PJ, Lam LT, Lee J, Maecker HL, Marsh KC, Mason KD, Mitten MJ, Nimmer PM, Oleksijew A, Park CH, Park CM, Phillips DC, Roberts AW, Sampath D, Seymour JF, Smith ML, Sullivan GM, Tahir SK, Tse C, Wendt MD, Xiao Y, Xue JC, Zhang H, Humerickhouse RA, Rosenberg SH, Elmore SW (2013) ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 19(2):202–208PubMedCrossRef

go back to reference Anderson MA, Deng J, Seymour JF, Tam C, Kim SY, Fein J, Yu L, Brown JR, Westerman D, Si EG, Majewski IJ, Segal D, Heitner Enschede SL, Huang DC, Davids MS, Letai A, Roberts AW (2016) The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism. Blood 127(25):3215–3224PubMedPubMedCentralCrossRef Anderson MA, Deng J, Seymour JF, Tam C, Kim SY, Fein J, Yu L, Brown JR, Westerman D, Si EG, Majewski IJ, Segal D, Heitner Enschede SL, Huang DC, Davids MS, Letai A, Roberts AW (2016) The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism. Blood 127(25):3215–3224PubMedPubMedCentralCrossRef

go back to reference Gadek TR, Burdick DJ, McDowell RS, Stanley MS, Marsters JC Jr, Paris KJ, Oare DA, Reynolds ME, Ladner C, Zioncheck KA, Lee WP, Gribling P, Dennis MS, Skelton NJ, Tumas DB, Clark KR, Keating SM, Beresini MH, Tilley JW, Presta LG, Bodary SC (2002) Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule. Science 295(5557):1086–1089PubMedCrossRef Gadek TR, Burdick DJ, McDowell RS, Stanley MS, Marsters JC Jr, Paris KJ, Oare DA, Reynolds ME, Ladner C, Zioncheck KA, Lee WP, Gribling P, Dennis MS, Skelton NJ, Tumas DB, Clark KR, Keating SM, Beresini MH, Tilley JW, Presta LG, Bodary SC (2002) Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule. Science 295(5557):1086–1089PubMedCrossRef

go back to reference Zhong M, Shen W, Barr KJ, Arbitrario JP, Arkin MR, Bui M, Chen T, Cunningham BC, Evanchik MJ, Hanan EJ, Hoch U, Huen K, Hyde J, Kumer JL, Lac T, Lawrence CE, Martell JR, Oslob JD, Paulvannan K, Prabhu S, Silverman JA, Wright J, Yu CH, Zhu J, Flanagan WM (2010) Discovery of tetrahydroisoquinoline (THIQ) derivatives as potent and orally bioavailable LFA-1/ICAM-1 antagonists. Bioorg Med Chem Lett 20(17):5269–5273PubMedCrossRef Zhong M, Shen W, Barr KJ, Arbitrario JP, Arkin MR, Bui M, Chen T, Cunningham BC, Evanchik MJ, Hanan EJ, Hoch U, Huen K, Hyde J, Kumer JL, Lac T, Lawrence CE, Martell JR, Oslob JD, Paulvannan K, Prabhu S, Silverman JA, Wright J, Yu CH, Zhu J, Flanagan WM (2010) Discovery of tetrahydroisoquinoline (THIQ) derivatives as potent and orally bioavailable LFA-1/ICAM-1 antagonists. Bioorg Med Chem Lett 20(17):5269–5273PubMedCrossRef

go back to reference Zhong CX, Wu JX, Liang JX, Wu QH (2012) Laparoscopic and gasless laparoscopic sigmoid colon vaginoplasty in women with vaginal agenesis. Chin Med J (Engl) 125(2):203–208 Zhong CX, Wu JX, Liang JX, Wu QH (2012) Laparoscopic and gasless laparoscopic sigmoid colon vaginoplasty in women with vaginal agenesis. Chin Med J (Engl) 125(2):203–208