Allosteric Modulators of Protein–Protein Interactions (PPIs)

  • Duan Ni
  • Na Liu
  • Chunquan ShengEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1163)


Protein–protein interactions (PPIs) represent promising drug targets of broad-spectrum therapeutic interests due to their critical implications in both health and disease circumstances. Hence, they are widely accepted as the Holy Grail of drug development. Historically, PPIs were rendered “undruggable” for their large, flat, and pocket-less structures. Current attempts to drug these “intractable” targets include orthosteric and allosteric methodologies. Previous efforts employing orthosteric approaches like protein therapeutics and orthosteric small molecules frequently suffered from poor performance caused by the difficulties in directly targeting PPI interfaces. As structural biology progresses rapidly, allosteric modulators, which direct to the allosteric regulatory sites remote to the PPI surfaces, have gradually established as a potential solution. Allosteric pockets are topologically distal from the PPI orthosteric sites, and their ligands do not need to compete with the PPI partners, which helps to improve the physiochemical and pharmacological properties of allosteric PPI modulators. Thus, exploiting allostery to tailor PPIs is regarded as a tempting strategy in future PPI drug discovery. Here, we provide a comprehensive review of our representative achievements along the way we utilize allosteric effects to tame the difficult PPI systems into druggable targets. Importantly, we provide an in-depth mechanistic analysis of this success, which will be instructive to future related lead optimizations and drug design. Finally, we discuss the current challenges in allosteric PPI drug discovery. Their solutions as well as future perspectives are also presented.


Protein–protein interaction Allostery Allosteric modulator Drug design 


  1. 1.
    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):4640–4694PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Alushin GM, Lander GC, Kellogg EH, Zhang R, Baker D, Nogales E (2014) High-resolution microtubule structures reveal the structural transitions in alphabeta-tubulin upon GTP hydrolysis. Cell 157(5):1117–1129PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Antoniades C, Bakogiannis C, Tousoulis D, Antonopoulos AS, Stefanadis C (2009) The CD40/CD40 ligand system: linking inflammation with atherothrombosis. J Am Coll Cardiol 54(8):669–677PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Arkin MR, Tang Y, Wells JA (2014) Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. Chem Biol 21(9):1102–1114PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Arkin MR, Wells JA (2004) Small-molecule inhibitors of protein-protein interactions: progressing towards the dream. Nat Rev Drug Discov 3(4):301–317PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Bahadur RP, Zacharias M (2008) The interface of protein-protein complexes: analysis of contacts and prediction of interactions. Cell Mol Life Sci 65(7–8):1059–1072PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Bedford L, Lowe J, Dick LR, Mayer RJ, Brownell JE (2011) Ubiquitin-like protein conjugation and the ubiquitin-proteasome system as drug targets. Nat Rev Drug Discov 10(1):29–46PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Bellmunt J, Szczylik C, Feingold J, Strahs A, Berkenblit A (2008) Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features. Ann Oncol 19(8):1387–1392PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Bloom J, Cross FR (2007) Multiple levels of cyclin specificity in cell-cycle control. Nat Rev Mol Cell Biol 8(2):149–160PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    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):955–959PubMedGoogle Scholar
  11. 11.
    Boumpas DT, Furie R, Manzi S, Illei GG, Wallace DJ, Balow JE, Vaishnaw A, Group BGLNT (2003) A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum 48(3):719–727PubMedCrossRefGoogle Scholar
  12. 12.
    Cao YN, Zheng LL, Wang D, Liang XX, Gao F, Zhou XL (2018) Recent advances in microtubule-stabilizing agents. Eur J Med Chem 143:806–828PubMedCrossRefGoogle Scholar
  13. 13.
    Ceccarelli DF, Tang X, Pelletier B, Orlicky S, Xie W, Plantevin V, Neculai D, Chou YC, Ogunjimi A, Al-Hakim A, Varelas X, Koszela J, Wasney GA, Vedadi M, Dhe-Paganon S, Cox S, Xu S, Lopez-Girona A, Mercurio F, Wrana J, Durocher D, Meloche S, Webb DR, Tyers M, Sicheri F (2011) An allosteric inhibitor of the human Cdc34 ubiquitin-conjugating enzyme. Cell 145(7):1075–1087PubMedCrossRefGoogle Scholar
  14. 14.
    Changeux JP (2013) The concept of allosteric modulation: an overview. Drug Discov Today Technol 10(2):e223–e228PubMedCrossRefGoogle Scholar
  15. 15.
    Chen Q, Xie W, Kuhn DJ, Voorhees PM, Lopez-Girona A, Mendy D, Corral LG, Krenitsky VP, Xu W, Moutouh-de Parseval L, Webb DR, Mercurio F, Nakayama KI, Nakayama K, Orlowski RZ (2008) Targeting the p27 E3 ligase SCF(Skp2) results in p27- and Skp2-mediated cell-cycle arrest and activation of autophagy. Blood 111(9):4690–4699PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    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):71–75PubMedCrossRefGoogle Scholar
  17. 17.
    Cheng KY, Noble ME, Skamnaki V, Brown NR, Lowe ED, Kontogiannis L, Shen K, Cole PA, Siligardi G, Johnson LN (2006) The role of the phospho-CDK2/cyclin a recruitment site in substrate recognition. J Biol Chem 281(32):23167–23179PubMedCrossRefGoogle Scholar
  18. 18.
    Cho CS, Burkly LC, Fechner JH Jr, Kirk AD, Oberley TD, Dong Y, Brunner KG, Peters D, Tenhoor CN, Nadeau K, Yagci G, Ishido N, Schultz JM, Tsuchida M, Hamawy MM, Knechtle SJ (2001) Successful conversion from conventional immunosuppression to anti-CD154 monoclonal antibody costimulatory molecule blockade in rhesus renal allograft recipients. Transplantation 72(4):587–597PubMedCrossRefGoogle Scholar
  19. 19.
    Cirillo L, Gotta M, Meraldi P (2017) The elephant in the room: the role of microtubules in Cancer. Adv Exp Med Biol 1002:93–124PubMedCrossRefGoogle Scholar
  20. 20.
    Cohen P, Tcherpakov M (2010) Will the ubiquitin system furnish as many drug targets as protein kinases? Cell 143(5):686–693PubMedCrossRefGoogle Scholar
  21. 21.
    Cong X, Liu Y, Liu W, Liang X, Laganowsky A (2017) Allosteric modulation of protein-protein interactions by individual lipid binding events. Nat Commun 8(1):2203PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Corbi-Verge C, Garton M, Nim S, Kim PM (2017) Strategies to develop inhibitors of motif-mediated protein-protein interactions as drug leads. Annu Rev Pharmacol Toxicol 57:39–60PubMedCrossRefGoogle Scholar
  23. 23.
    Cossins BP, Lawson AD (2015) Small molecule targeting of protein-protein interactions through allosteric modulation of dynamics. Molecules 20(9):16435–16445PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Costanzo M, Nishikawa JL, Tang X, Millman JS, Schub O, Breitkreuz K, Dewar D, Rupes I, Andrews B, Tyers M (2004) CDK activity antagonizes Whi5, an inhibitor of G1/S transcription in yeast. Cell 117(7):899–913PubMedCrossRefGoogle Scholar
  25. 25.
    Crown J, O’Leary M (2000) The taxanes: an update. Lancet 355(9210):1176–1178PubMedCrossRefGoogle Scholar
  26. 26.
    Daikh DI, Finck BK, Linsley PS, Hollenbaugh D, Wofsy D (1997) Long-term inhibition of murine lupus by brief simultaneous blockade of the B7/CD28 and CD40/gp39 costimulation pathways. J Immunol 159(7):3104–3108PubMedGoogle Scholar
  27. 27.
    Darieva Z, Pic-Taylor A, Boros J, Spanos A, Geymonat M, Reece RJ, Sedgwick SG, Sharrocks AD, Morgan BA (2003) Cell cycle-regulated transcription through the FHA domain of Fkh2p and the coactivator Ndd1p. Curr Biol 13(19):1740–1745PubMedCrossRefGoogle Scholar
  28. 28.
    de Bruin RA, McDonald WH, Kalashnikova TI, Yates J 3rd, Wittenberg C (2004) Cln3 activates G1-specific transcription via phosphorylation of the SBF bound repressor Whi5. Cell 117(7):887–898PubMedCrossRefGoogle Scholar
  29. 29.
    Dobashi Y (2005) Cell cycle regulation and its aberrations in human lung carcinoma. Pathol Int 55(3):95–105PubMedCrossRefGoogle Scholar
  30. 30.
    Dumontet C, Jordan MA (2010) Microtubule-binding agents: a dynamic field of cancer therapeutics. Nat Rev Drug Discov 9(10):790–803PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Echalier A, Endicott JA, Noble ME (2010) Recent developments in cyclin-dependent kinase biochemical and structural studies. Biochim Biophys Acta 1804(3):511–519PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Elgueta R, Benson MJ, de Vries VC, Wasiuk A, Guo Y, Noelle RJ (2009) Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev 229(1):152–172PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Emanuel S, Rugg CA, Gruninger RH, Lin R, Fuentes-Pesquera A, Connolly PJ, Wetter SK, Hollister B, Kruger WW, Napier C, Jolliffe L, Middleton SA (2005) The in vitro and in vivo effects of JNJ-7706621: a dual inhibitor of cyclin-dependent kinases and aurora kinases. Cancer Res 65(19):9038–9046PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Ferrant JL, Benjamin CD, Cutler AH, Kalled SL, Hsu YM, Garber EA, Hess DM, Shapiro RI, Kenyon NS, Harlan DM, Kirk AD, Burkly LC, Taylor FR (2004) The contribution of Fc effector mechanisms in the efficacy of anti-CD154 immunotherapy depends on the nature of the immune challenge. Int Immunol 16(11):1583–1594PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Field JJ, Diaz JF, Miller JH (2013) The binding sites of microtubule-stabilizing agents. Chem Biol 20(3):301–315PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Fischer PM (2004) The use of CDK inhibitors in oncology: a pharmaceutical perspective. Cell Cycle 3(6):742–746PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Fischer G, Rossmann M, Hyvonen M (2015) Alternative modulation of protein-protein interactions by small molecules. Curr Opin Biotechnol 35:78–85PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47(7):1739–1749PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Fry DC (2008) Drug-like inhibitors of protein-protein interactions: a structural examination of effective protein mimicry. Curr Protein Pept Sci 9(3):240–247PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Galsky MD, Dritselis A, Kirkpatrick P, Oh WK (2010) Cabazitaxel. Nat Rev Drug Discov 9(9):677–678PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Guarnera E, Berezovsky IN (2016) Allosteric sites: remote control in regulation of protein activity. Curr Opin Struct Biol 37:1–8PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Guarnera E, Tan ZW, Zheng Z, Berezovsky IN (2017) AlloSigMA: allosteric signaling and mutation analysis server. Bioinformatics 33(24):3996–3998PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674CrossRefGoogle Scholar
  44. 44.
    Heery CR, Ibrahim NK, Arlen PM, Mohebtash M, Murray JL, Koenig K, Madan RA, McMahon S, Marte JL, Steinberg SM, Donahue RN, Grenga I, Jochems C, Farsaci B, Folio LR, Schlom J, Gulley JL (2015) Docetaxel alone or in combination with a therapeutic cancer vaccine (PANVAC) in patients with metastatic breast cancer: a randomized clinical trial. JAMA Oncol 1(8):1087–1095PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Holland EJ, Luchs J, Karpecki PM, Nichols KK, Jackson MA, Sall K, Tauber J, Roy M, Raychaudhuri A, Shojaei A (2017) Lifitegrast for the treatment of dry eye disease: results of a phase III, randomized, double-masked, placebo-controlled trial (OPUS-3). Ophthalmology 124(1):53–60PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Hu Y, Li S, Liu F, Geng L, Shu X, Zhang J (2015) Discovery of novel nonpeptide allosteric inhibitors interrupting the interaction of CDK2/cyclin A3 by virtual screening and bioassays. Bioorg Med Chem Lett 25(19):4069–4073PubMedCrossRefGoogle Scholar
  47. 47.
    Huang M, Song K, Liu X, Lu S, Shen Q, Wang R, Gao J, Hong Y, Li Q, Ni D, Xu J, Chen G, Zhang J (2018) AlloFinder: a strategy for allosteric modulator discovery and allosterome analyses. Nucleic Acids Res 46(W1):W451–W458PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Huang W, Lu S, Huang Z, Liu X, Mou L, Luo Y, Zhao Y, Liu Y, Chen Z, Hou T, Zhang J (2013) Allosite: a method for predicting allosteric sites. Bioinformatics 29(18):2357–2359PubMedCrossRefGoogle Scholar
  49. 49.
    James ND, Pirrie SJ, Pope AM, Barton D, Andronis L, Goranitis I, Collins S, Daunton A, McLaren D, O’Sullivan J, Parker C, Porfiri E, Staffurth J, Stanley A, Wylie J, Beesley S, Birtle A, Brown J, Chakraborti P, Hussain S, Russell M, Billingham LJ (2016) Clinical outcomes and survival following treatment of metastatic castrate-refractory prostate cancer with docetaxel alone or with strontium-89, zoledronic acid, or both: the TRAPEZE randomized clinical trial. JAMA Oncol 2(4):493–499PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Jiang Y, Zhuang C, Chen L, Lu J, Dong G, Miao Z, Zhang W, Li J, Sheng C (2017) Structural biology-inspired discovery of novel KRAS–PDEδ inhibitors. J Med Chem 60:9400–9406PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Jin L, Wang W, Fang G (2014) Targeting protein-protein interaction by small molecules. Annu Rev Pharmacol Toxicol 54:435–456PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Jones S, Thornton JM (1996) Principles of protein-protein interactions. Proc Natl Acad Sci U S A 93(1):13–20PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Jordan MA, Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 4(4):253–265PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Jurgens G, Hermann A, Aktuna D, Petek W (1992) Dissociation-enhanced lanthanide fluorescence immunoassay of lipoprotein(a) in serum. Clin Chem 38(6):853–859PubMedPubMedCentralGoogle Scholar
  55. 55.
    Karthiga A, Tripathi SK, Shanmugam R, Suryanarayanan V, Singh SK (2015) Targeting the cyclin-binding groove site to inhibit the catalytic activity of CDK2/cyclin a complex using p27(KIP1)-derived peptidomimetic inhibitors. J Chem Biol 8(1):11–24PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Kim WK, Henschel A, Winter C, Schroeder M (2006) The many faces of protein-protein interactions: a compendium of interface geometry. PLoS Comput Biol 2(9):e124PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Komander D, Rape M (2012) The ubiquitin code. Annu Rev Biochem 81:203–229PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Koya K, Li Y, Wang H, Ukai T, Tatsuta N, Kawakami M, Shishido CLB (1996) MKT-077, a novel rhodacyanine dye in clinical trials, exhibits anticarcinoma activity in preclinical studies based on selective mitochondrial accumulation. Cancer Res 56(3):538–543PubMedPubMedCentralGoogle Scholar
  59. 59.
    Laganowsky A, Reading E, Allison TM, Ulmschneider MB, Degiacomi MT, Baldwin AJ, Robinson CV (2014) Membrane proteins bind lipids selectively to modulate their structure and function. Nature 510(7503):172–175PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Lee FY, Borzilleri R, Fairchild CR, Kim SH, Long BH, Reventos-Suarez C, Vite GD, Rose WC, Kramer RA (2001) BMS-247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin Cancer Res 7(5):1429–1437PubMedPubMedCentralGoogle Scholar
  61. 61.
    Li X, Chen Y, Lu S, Huang Z, Liu X, Wang Q, Shi T, Zhang J (2013) Toward an understanding of the sequence and structural basis of allosteric proteins. J Mol Graph Model 40:30–39PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Liu N, Tu J, Dong G, Wang Y, Sheng C (2018) Emerging new targets for the treatment of resistant fungal infections. J Med Chem 61:5484–5511PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Liu N, Zhu S, Zhang X, Yin X, Dong G, Yao J, Miao Z, Zhang W, Zhang X, Sheng C (2016) The discovery and characterization of a novel scaffold as a potent hepatitis C virus inhibitor. Chem Commun 52:3340–3343CrossRefGoogle Scholar
  64. 64.
    Lo Conte L, Chothia C, Janin J (1999) The atomic structure of protein-protein recognition sites. J Mol Biol 285(5):2177–2198PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Lu S, Huang W, Zhang J (2014a) Recent computational advances in the identification of allosteric sites in proteins. Drug Discov Today 19(10):1595–1600PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Lu S, Li S, Zhang J (2014b) Harnessing allostery: a novel approach to drug discovery. Med Res Rev 34(6):1242–1285PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Lu S, Zhang J (2018) Small molecule allosteric modulators of G-protein-coupled receptors: drug-target interactions. J Med Chem. Scholar
  68. 68.
    Malumbres M (2014) Cyclin-dependent kinases. Genome Biol 15(6):122PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Malumbres M, Barbacid M (2001) To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer 1(3):222–231PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Malumbres M, Barbacid M (2005) Mammalian cyclin-dependent kinases. Trends Biochem Sci 30(11):630–641PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Mekhail TM, Markman M (2002) Paclitaxel in cancer therapy. Expert Opin Pharmacother 3(6):755–766PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Merk A, Bartesaghi A, Banerjee S, Falconieri V, Rao P, Davis MI, Pragani R, Boxer MB, Earl LA, Milne JLS, Subramaniam S (2016) Breaking Cryo-EM resolution barriers to facilitate drug discovery. Cell 165(7):1698–1707PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Miao Z, Ali A, Hu L, Zhao F, Yin C, Chen C, Yang T, Qian A (2017) Microtubule actin cross-linking factor 1, a novel potential target in cancer. Cancer Sci 108(10):1953–1958PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    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 Eng 54(52):15720–15724CrossRefGoogle Scholar
  75. 75.
    Mita AC, Denis LJ, Rowinsky EK, Debono JS, Goetz AD, Ochoa L, Forouzesh B, Beeram M, Patnaik A, Molpus K, Semiond D, Besenval M, Tolcher AW (2009) Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors. Clin Cancer Res 15(2):723–730PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Mitra A, Sept D (2008) Taxol allosterically alters the dynamics of the tubulin dimer and increases the flexibility of microtubules. Biophys J 95(7):3252–3258PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Morgan DO (1997) Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu Rev Cell Dev Biol 13:261–291PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Morris PG (2010) Advances in therapy: eribulin improves survival for metastatic breast cancer. Anti-Cancer Drugs 21(10):885–889PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Mullard A (2012) Protein-protein interaction inhibitors get into the groove. Nat Rev Drug Discov 11(3):173–175PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL (2011) Cyclin D as a therapeutic target in cancer. Nat Rev Cancer 11(8):558–572PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Nabholtz JM, Gligorov J (2005) The role of taxanes in the treatment of breast cancer. Expert Opin Pharmacother 6(7):1073–1094PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Nalepa G, Rolfe M, Harper JW (2006) Drug discovery in the ubiquitin-proteasome system. Nat Rev Drug Discov 5(7):596–613PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Nero TL, Morton CJ, Holien JK, Wielens J, Parker MW (2014) Oncogenic protein interfaces: small molecules, big challenges. Nat Rev Cancer 14(4):248–262PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Nussinov R, Tsai CJ (2013) Allostery in disease and in drug discovery. Cell 153(2):293–305PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Nussinov R, Tsai CJ, Csermely P (2011) Allo-network drugs: harnessing allostery in cellular networks. Trends Pharmacol Sci 32(12):686–693PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Olziersky AM, Labidi-Galy SI (2017) Clinical development of anti-mitotic drugs in cancer. Adv Exp Med Biol 1002:125–152PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Osborne C, Challagalla JD, Eisenbeis CF, Holmes FA, Neubauer MA, Koutrelakos NW, Taboada CA, Vukelja SJ, Wilks ST, Allison MA, Reddy P, Sedlacek S, Wang Y, Asmar L, O’Shaughnessy J (2018) Ixabepilone and carboplatin for hormone receptor positive/HER2-neu negative and triple negative metastatic breast cancer. Clin Breast Cancer 18(1):e89–e95PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Ottaggio L, Bestoso F, Armirotti A, Balbi A, Damonte G, Mazzei M, Sancandi M, Miele M (2008) Taxanes from shells and leaves of Corylus avellana. J Nat Prod 71(1):58–60PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Panjkovich A, Daura X (2014) PARS: a web server for the prediction of protein allosteric and regulatory sites. Bioinformatics 30(9):1314–1315PubMedCrossRefGoogle Scholar
  90. 90.
    Pegoraro AF, Janmey P, Weitz DA (2017) Mechanical properties of the cytoskeleton and cells. Cold Spring Harb Perspect Biol 9(11):a022038PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Plumb JA (2004) Cell sensitivity assays: the MTT assay. Methods Mol Med 88:165–169PubMedGoogle Scholar
  92. 92.
    Propper DJ, Braybrooke JP, Taylor DJ, Lodi R, Styles P, Cramer JA, Collins WC, Levitt NC, Talbot DC, Ganesan TS, Harris AL (1999) Phase I trial of the selective mitochondrial toxin MKT077 in chemo-resistant solid tumours. Ann Oncol 10(8):923–927PubMedCrossRefGoogle Scholar
  93. 93.
    Quezada SA, Jarvinen LZ, Lind EF, Noelle RJ (2004) CD40/CD154 interactions at the interface of tolerance and immunity. Annu Rev Immunol 22:307–328PubMedCrossRefGoogle Scholar
  94. 94.
    Reynolds D, Shi BJ, McLean C, Katsis F, Kemp B, Dalton S (2003) Recruitment of Thr 319-phosphorylated Ndd1p to the FHA domain of Fkh2p requires Clb kinase activity: a mechanism for CLB cluster gene activation. Genes Dev 17(14):1789–1802PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Richardson DL, Sill MW, Coleman RL, Sood AK, Pearl ML, Kehoe SM, Carney ME, Hanjani P, Van Le L, Zhou XC, Alvarez Secord A, Gray HJ, Landrum LM, Lankes HA, Hu W, Aghajanian C (2018) Paclitaxel with and without Pazopanib for persistent or recurrent ovarian cancer: a randomized clinical trial. JAMA Oncol 4(2):196–202PubMedCrossRefGoogle Scholar
  96. 96.
    Roskoski R Jr (2016) Cyclin-dependent protein kinase inhibitors including palbociclib as anticancer drugs. Pharmacol Res 107:249–275PubMedCrossRefGoogle Scholar
  97. 97.
    Rouhana J, Padilla A, Estaran S, Bakari S, Delbecq S, Boublik Y, Chopineau J, Pugniere M, Chavanieu A (2013) Kinetics of interaction between ADP-ribosylation factor-1 (Arf1) and the Sec7 domain of Arno guanine nucleotide exchange factor, modulation by allosteric factors, and the uncompetitive inhibitor brefeldin A. J Biol Chem 288(7):4659–4672PubMedCrossRefGoogle Scholar
  98. 98.
    Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (2005) Towards a proteome-scale map of the human protein-protein interaction network. Nature 437(7062):1173–1178PubMedCrossRefGoogle Scholar
  99. 99.
    Saloustros E, Mavroudis D, Georgoulias V (2008) Paclitaxel and docetaxel in the treatment of breast cancer. Expert Opin Pharmacother 9(15):2603–2616PubMedCrossRefGoogle Scholar
  100. 100.
    Schiff PB, Fant J, Horwitz SB (1979) Promotion of microtubule assembly in vitro by taxol. Nature 277(5698):665–667PubMedCrossRefGoogle Scholar
  101. 101.
    Schiff PB, Horwitz SB (1980) Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci U S A 77(3):1561–1565PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Schulze M, Stock C, Zaccagnini M, Teber D, Rassweiler JJ (2014) Temsirolimus. Recent Results Cancer Res 201:393–403PubMedCrossRefGoogle Scholar
  103. 103.
    Schwabe RF, Hess S, Johnson JP, Engelmann H (1997) Modulation of soluble CD40 ligand bioactivity with anti-CD40 antibodies. Hybridoma 16(3):217–226PubMedCrossRefGoogle Scholar
  104. 104.
    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):533–550PubMedCrossRefGoogle Scholar
  105. 105.
    Shen Q, Wang G, Li S, Liu X, Lu S, Chen Z, Song K, Yan J, Geng L, Huang Z, Huang W, Chen G, Zhang J (2016) ASD v3.0: unraveling allosteric regulation with structural mechanisms and biological networks. Nucleic Acids Res 44(D1):D527–D535PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    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):8238–8259PubMedCrossRefGoogle Scholar
  107. 107.
    Sho M, Sandner SE, Najafian N, Salama AD, Dong V, Yamada A, Kishimoto K, Harada H, Schmitt I, Sayegh MH (2002) New insights into the interactions between T-cell costimulatory blockade and conventional immunosuppressive drugs. Ann Surg 236(5):667–675PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Silvian LF, Friedman JE, Strauch K, Cachero TG, Day ES, Qian F, Cunningham B, Fung A, Sun L, Shipps GW, Su L, Zheng Z, Kumaravel G, Whitty A (2011) Small molecule inhibition of the TNF family cytokine CD40 ligand through a subunit fracture mechanism. ACS Chem Biol 6(6):636–647PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    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:e16PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksoz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE (2005) A human protein-protein interaction network: a resource for annotating the proteome. Cell 122(6):957–968PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    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 U S A 105(19):6959–6964PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Suchard SJ, Stetsko DK, Davis PM, Skala S, Potin D, Launay M, Dhar TG, Barrish JC, Susulic V, Shuster DJ, McIntyre KW, McKinnon M, Salter-Cid L (2010) An LFA-1 (alphaLbeta2) small-molecule antagonist reduces inflammation and joint destruction in murine models of arthritis. J Immunol 184(7):3917–3926PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Thiel P, Kaiser M, Ottmann C (2012) Small-molecule stabilization of protein-protein interactions: an underestimated concept in drug discovery? Angew Chem Int Ed Eng 51(9):2012–2018CrossRefGoogle Scholar
  114. 114.
    Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsky BM, Palme MH, Habgood GJ, Singer LA, Dipietro LV, Wang Y, Chen JJ, Quincy DA, Davis A, Yoshimatsu K, Kishi Y, Yu MJ, Littlefield BA (2001) In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res 61(3):1013–1021PubMedPubMedCentralGoogle Scholar
  115. 115.
    van Westen GJ, Gaulton A, Overington JP (2014) Chemical, target, and bioactive properties of allosteric modulation. PLoS Comput Biol 10(4):e1003559PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    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):83–90PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    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):466–469PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Wagner JR, Lee CT, Durrant JD, Malmstrom RD, Feher VA, Amaro RE (2016) Emerging computational methods for the rational discovery of allosteric drugs. Chem Rev 116(11):6370–6390PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Wang Q, Zheng M, Huang Z, Liu X, Zhou H, Chen Y, Shi T, Zhang J (2012) Toward understanding the molecular basis for chemical allosteric modulator design. J Mol Graph Model 38:324–333PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT (1971) Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc 93(9):2325–2327PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Watterson SH, Xiao Z, Dodd DS, Tortolani DR, Vaccaro W, Potin D, Launay M, Stetsko DK, Skala S, Davis PM, Lee D, Yang X, KW MI, Balimane P, Patel K, Yang Z, Marathe P, Kadiyala P, Tebben AJ, Sheriff S, Chang CY, Ziemba T, Zhang H, Chen BC, Del Monte 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):3814–3830PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Wells JA, McClendon CL (2007) Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 450(7172):1001–1009PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Whitty A, Kumaravel G (2006) Between a rock and a hard place? Nat Chem Biol 2(3):112–118PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Yau R, Rape M (2016) The increasing complexity of the ubiquitin code. Nat Cell Biol 18(6):579–586PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    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):48–57PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    Zhang B, Wu T, Chen M, Zhou Y, Yi D, Guo R (2013) The CD40/CD40L system: a new therapeutic target for disease. Immunol Lett 153(1–2):58–61PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Zhong M, Gadek TR, Bui M, Shen W, Burnier J, Barr KJ, Hanan EJ, Oslob JD, Yu CH, Zhu J, Arkin MR, Evanchik MJ, Flanagan WM, Hoch U, Hyde J, Prabhu S, Silverman JA, Wright J (2012) Discovery and development of potent LFA-1/ICAM-1 antagonist SAR 1118 as an ophthalmic solution for treating dry eye. ACS Med Chem Lett 3(3):203–206PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Zhuang C, Miao Z, Sheng C, Zhang W (2014a) Updated research and applications of small molecule inhibitors of Keap1-Nrf2 protein-protein interaction: a review. Curr Med Chem 21:1861–1870PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Zhuang C, Miao Z, Wu Y, Guo Z, Li J, Yao J, Xing C, Sheng C, Zhang W (2014b) Double-edged swords as cancer therapeutics: novel, orally active, small molecules simultaneously inhibit p53–MDM2 interaction and the NF-κB pathway. J Med Chem 57:567–577PubMedCrossRefGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
  2. 2.School of PharmacySecond Military Medical UniversityShanghaiChina

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