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

Zurück zum Zitat 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

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Zurück zum Zitat 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

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Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

Zurück zum Zitat 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

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Zurück zum Zitat 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

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Zurück zum Zitat 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

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