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High-Throughput Screening in the Discovery of Small-Molecule Inhibitors of Protein-Protein Interactions

  • Chunlin Zhuang
  • Chunquan Sheng
Chapter

Abstract

High-throughput screening (HTS) is an important method to discover small-molecule inhibitors of protein-protein interactions. The construction of HTS compatible assays and compounds libraries plays a key role in successful identification of PPI inhibitors. Strategies for compound library design and assay establishment as well as their advantages and limitations will be introduced. Two successful case studies about HTS of p53–MDM2 and PDEδ–KRAS inhibitors are highlighted.

Keywords

High-throughput screening Multi-component reaction Diversity-oriented synthesis Cascade reaction Fluorescence polarization Fluorescence resonance energy transfer AlphaScreen p53–MDM2 PDEδ–KRAS 

References

  1. 1.
    Arkin MR, Wells JA (2004) Small-molecule inhibitors of protein-protein interactions: progressing towards the dream. Nat Rev Drug Discov 3(4):301–317PubMedGoogle Scholar
  2. 2.
    Fry DC (2008) Drug-like inhibitors of protein-protein interactions: a structural examination of effective protein mimicry. Curr Protein Pept Sci 9(3):240–247PubMedGoogle Scholar
  3. 3.
    Whitty A, Kumaravel G (2006) Between a rock and a hard place? Nat Chem Biol 2(3):112–118PubMedGoogle Scholar
  4. 4.
    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):8238–8259PubMedGoogle Scholar
  5. 5.
    Cheng T, Li Q, Zhou Z, Wang Y, Bryant SH (2012) Structure-based virtual screening for drug discovery: a problem-centric review. AAPS J 14(1):133–141PubMedPubMedCentralGoogle Scholar
  6. 6.
    Heeres JT, Hergenrother PJ (2011) High-throughput screening for modulators of protein-protein interactions: use of photonic crystal biosensors and complementary technologies. Chem Soc Rev 40(8):4398–4410PubMedGoogle Scholar
  7. 7.
    Gul S, Hadian K (2014) Protein-protein interaction modulator drug discovery: past efforts and future opportunities using a rich source of low- and high-throughput screening assays. Expert Opin Drug Discov 9(12):1393–1404PubMedGoogle Scholar
  8. 8.
    Adler-Moore JP, Gangneux JP, Pappas PG (2016) Comparison between liposomal formulations of amphotericin B. Med Mycol 54(3):223–231PubMedGoogle Scholar
  9. 9.
    Choi S, Choi KY (2017) Screening-based approaches to identify small molecules that inhibit protein-protein interactions. Expert Opin Drug Discov 12(3):293–303PubMedGoogle Scholar
  10. 10.
    Ruijter E, Scheffelaar R, Orru RV (2011) Multicomponent reaction design in the quest for molecular complexity and diversity. Angew Chem Int Ed Engl 50(28):6234–6246PubMedGoogle Scholar
  11. 11.
    Antuch W, Menon S, Chen QZ, Lu Y, Sakamuri S, Beck B, Schauer-Vukasinovic V, Agarwal S, Hess S, Domling A (2006) Design and modular parallel synthesis of a MCR derived alpha-helix mimetic protein-protein interaction inhibitor scaffold. Bioorg Med Chem Lett 16(6):1740–1743PubMedGoogle Scholar
  12. 12.
    Xu Y, Lu H, Kennedy JP, Yan X, McAllister LA, Yamamoto N, Moss JA, Boldt GE, Jiang S, Janda KD (2006) Evaluation of “credit card” libraries for inhibition of HIV-1 gp41 fusogenic core formation. J Comb Chem 8(4):531–539PubMedPubMedCentralGoogle Scholar
  13. 13.
    Monfardini I, Huang JW, Beck B, Cellitti JF, Pellecchia M, Domling A (2011) Screening multicomponent reactions for X-linked inhibitor of apoptosis-baculoviral inhibitor of apoptosis protein repeats domain binder. J Med Chem 54(3):890–900PubMedGoogle Scholar
  14. 14.
    Boltjes A, Huang Y, van de Velde R, Rijkee L, Wolf S, Gaugler J, Lesniak K, Guzik K, Holak TA, Domling A (2014) Fragment-based library generation for the discovery of a peptidomimetic p53-Mdm4 inhibitor. ACS Comb Sci 16(8):393–396PubMedPubMedCentralGoogle Scholar
  15. 15.
    Czarna A, Beck B, Srivastava S, Popowicz GM, Wolf S, Huang Y, Bista M, Holak TA, Domling A (2010) Robust generation of lead compounds for protein-protein interactions by computational and MCR chemistry: p53/Hdm2 antagonists. Angew Chem Int Ed Engl 49(31):5352–5356PubMedPubMedCentralGoogle Scholar
  16. 16.
    Schreiber SL (2009) Organic chemistry: molecular diversity by design. Nature 457(7226):153–154PubMedGoogle Scholar
  17. 17.
    Koes D, Khoury K, Huang Y, Wang W, Bista M, Popowicz GM, Wolf S, Holak TA, Domling A, Camacho CJ (2012) Enabling large-scale design, synthesis and validation of small molecule protein-protein antagonists. PLoS ONE 7(3):e32839PubMedPubMedCentralGoogle Scholar
  18. 18.
    Cj OC, Beckmann HS, Spring DR (2012) Diversity-oriented synthesis: producing chemical tools for dissecting biology. Chem Soc Rev 41(12):4444–4456Google Scholar
  19. 19.
    Kim J, Kim H, Park SB (2014) Privileged structures: efficient chemical “navigators” toward unexplored biologically relevant chemical spaces. J Am Chem Soc 136(42):14629–14638PubMedGoogle Scholar
  20. 20.
    Nielsen TE, Schreiber SL (2008) Towards the optimal screening collection: a synthesis strategy. Angew Chem Int Ed Engl 47(1):48–56PubMedGoogle Scholar
  21. 21.
    Galloway WR, Isidro-Llobet A, Spring DR (2010) Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules. Nat Commun 1:80PubMedGoogle Scholar
  22. 22.
    Grossmann A, Bartlett S, Janecek M, Hodgkinson JT, Spring DR (2014) Diversity-oriented synthesis of drug-like macrocyclic scaffolds using an orthogonal organo- and metal catalysis strategy. Angew Chem Int Ed Engl 53(48):13093–13097PubMedGoogle Scholar
  23. 23.
    Beckmann HS, Nie F, Hagerman CE, Johansson H, Tan YS, Wilcke D, Spring DR (2013) A strategy for the diversity-oriented synthesis of macrocyclic scaffolds using multidimensional coupling. Nat Chem 5(10):861–867PubMedGoogle Scholar
  24. 24.
    Marsault E, Peterson ML (2011) Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery. J Med Chem 54(7):1961–2004PubMedGoogle Scholar
  25. 25.
    Rubin LL, de Sauvage FJ (2006) Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov 5(12):1026–1033PubMedGoogle Scholar
  26. 26.
    Stanton BZ, Peng LF, Maloof N, Nakai K, Wang X, Duffner JL, Taveras KM, Hyman JM, Lee SW, Koehler AN, Chen JK, Fox JL, Mandinova A, Schreiber SL (2009) A small molecule that binds Hedgehog and blocks its signaling in human cells. Nat Chem Biol 5(3):154–156PubMedPubMedCentralGoogle Scholar
  27. 27.
    Marcaurelle LA, Johannes C, Yohannes D, Tillotson BP, Mann D (2009) Diversity-oriented synthesis of a cytisine-inspired pyridone library leading to the discovery of novel inhibitors of Bcl-2. Bioorg Med Chem Lett 19(9):2500–2503PubMedGoogle Scholar
  28. 28.
    Zhang Y, Wang S, Wu S, Zhu S, Dong G, Miao Z, Yao J, Zhang W, Sheng C, Wang W (2013) Facile construction of structurally diverse thiazolidinedione-derived compounds via divergent stereoselective cascade organocatalysis and their biological exploratory studies. ACS Comb Sci 15(6):298–308PubMedGoogle Scholar
  29. 29.
    Zhang Y, Wu S, Wang S, Fang K, Dong G, Liu N, Miao Z, Yao J, Li J, Zhang W, Sheng C, Wang W (2015) Divergent cascade construction of skeletally diverse “Privileged” pyrazole-derived molecular architectures. Eur J Org Chem 9:2030–2037Google Scholar
  30. 30.
    Wang S, Jiang Y, Wu S, Dong G, Miao Z, Zhang W, Sheng C (2016) Meeting organocatalysis with drug discovery: asymmetric synthesis of 3,3′-Spirooxindoles fused with tetrahydrothiopyrans as novel p53-MDM2 inhibitors. Org Lett 18(5):1028–1031PubMedGoogle Scholar
  31. 31.
    Bon RS, Waldmann H (2010) Bioactivity-guided navigation of chemical space. Acc Chem Res 43(8):1103–1114PubMedGoogle Scholar
  32. 32.
    Wetzel S, Bon RS, Kumar K, Waldmann H (2011) Biology-oriented synthesis. Angew Chem Int Ed Engl 50(46):10800–10826PubMedGoogle Scholar
  33. 33.
    Svenda J, Sheremet M, Kremer L, Maier L, Bauer JO, Strohmann C, Ziegler S, Kumar K, Waldmann H (2015) Biology-oriented synthesis of a withanolide-inspired compound collection reveals novel modulators of hedgehog signaling. Angew Chem Int Ed Engl 54(19):5596–5602PubMedGoogle Scholar
  34. 34.
    Antonchick AP, Gerding-Reimers C, Catarinella M, Schurmann M, Preut H, Ziegler S, Rauh D, Waldmann H (2010) Highly enantioselective synthesis and cellular evaluation of spirooxindoles inspired by natural products. Nat Chem 2(9):735–740PubMedGoogle Scholar
  35. 35.
    Duckert H, Pries V, Khedkar V, Menninger S, Bruss H, Bird AW, Maliga Z, Brockmeyer A, Janning P, Hyman A, Grimme S, Schurmann M, Preut H, Hubel K, Ziegler S, Kumar K, Waldmann H (2011) Natural product-inspired cascade synthesis yields modulators of centrosome integrity. Nat Chem Biol 8(2):179–184PubMedGoogle Scholar
  36. 36.
    Wells JA, McClendon CL (2007) Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature 450(7172):1001–1009PubMedGoogle Scholar
  37. 37.
    Zhao HF, Kiyota T, Chowdhury S, Purisima E, Banville D, Konishi Y, Shen SH (2004) A mammalian genetic system to screen for small molecules capable of disrupting protein-protein interactions. Anal Chem 76(10):2922–2927PubMedGoogle Scholar
  38. 38.
    Makley LN, Gestwicki JE (2013) Expanding the number of ‘druggable’ targets: non-enzymes and protein-protein interactions. Chem Biol Drug Des 81(1):22–32PubMedPubMedCentralGoogle Scholar
  39. 39.
    Couturier C, Deprez B (2012) Setting up a bioluminescence resonance energy transfer high throughput screening assay to search for protein/protein interaction inhibitors in mammalian cells. Front Endocrinol (Lausanne) 3:100Google Scholar
  40. 40.
    Kenny CH, Ding W, Kelleher K, Benard S, Dushin EG, Sutherland AG, Mosyak L, Kriz R, Ellestad G (2003) Development of a fluorescence polarization assay to screen for inhibitors of the FtsZ/ZipA interaction. Anal Biochem 323(2):224–233PubMedGoogle Scholar
  41. 41.
    Emami KH, Nguyen C, Ma H, Kim DH, Jeong KW, Eguchi M, Moon RT, Teo JL, Kim HY, Moon SH, Ha JR, Kahn M (2004) A small molecule inhibitor of beta-catenin/CREB-binding protein transcription. Proc Natl Acad Sci USA 101(34):12682–12687PubMedPubMedCentralGoogle Scholar
  42. 42.
    Chen T, Kablaoui N, Little J, Timofeevski S, Tschantz WR, Chen P, Feng J, Charlton M, Stanton R, Bauer P (2009) Identification of small-molecule inhibitors of the JIP-JNK interaction. Biochem J 420(2):283–294PubMedGoogle Scholar
  43. 43.
    Stebbins JL, De SK, Machleidt T, Becattini B, Vazquez J, Kuntzen C, Chen LH, Cellitti JF, Riel-Mehan M, Emdadi A, Solinas G, Karin M, Pellecchia M (2008) Identification of a new JNK inhibitor targeting the JNK-JIP interaction site. Proc Natl Acad Sci USA 105(43):16809–16813PubMedPubMedCentralGoogle Scholar
  44. 44.
    Glanzer JG, Liu S, Oakley GG (2011) Small molecule inhibitor of the RPA70 N-terminal protein interaction domain discovered using in silico and in vitro methods. Bioorg Med Chem 19(8):2589–2595PubMedPubMedCentralGoogle Scholar
  45. 45.
    Hain AU, Bartee D, Sanders NG, Miller AS, Sullivan DJ, Levitskaya J, Meyers CF, Bosch J (2014) Identification of an Atg8-Atg3 protein-protein interaction inhibitor from the medicines for Malaria Venture Malaria Box active in blood and liver stage Plasmodium falciparum parasites. J Med Chem 57(11):4521–4531PubMedPubMedCentralGoogle Scholar
  46. 46.
    Hu L, Magesh S, Chen L, Wang L, Lewis TA, Chen Y, Khodier C, Inoyama D, Beamer LJ, Emge TJ, Shen J, Kerrigan JE, Kong AN, Dandapani S, Palmer M, Schreiber SL, Munoz B (2013) Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction. Bioorg Med Chem Lett 23(10):3039–3043PubMedPubMedCentralGoogle Scholar
  47. 47.
    Marcotte D, Zeng W, Hus JC, McKenzie A, Hession C, Jin P, Bergeron C, Lugovskoy A, Enyedy I, Cuervo H, Wang D, Atmanene C, Roecklin D, Vecchi M, Vivat V, Kraemer J, Winkler D, Hong V, Chao J, Lukashev M, Silvian L (2013) Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism. Bioorg Med Chem 21(14):4011–4019PubMedGoogle Scholar
  48. 48.
    Jameson DM, Ross JA (2010) Fluorescence polarization/anisotropy in diagnostics and imaging. Chem Rev 110(5):2685–2708PubMedPubMedCentralGoogle Scholar
  49. 49.
    Perrin F (1926) Polarisation of fluorescence and mean life of excited molecules. J Phys Radium 7(12):390–401Google Scholar
  50. 50.
    Albrecht AC (1961) Polarizations and assignments of transitions: the method of photoselection. J Mol Spectrosc 6:84–108Google Scholar
  51. 51.
    Weber G (1953) Rotational Brownian motion and polarization of the fluorescence of solutions. Adv Protein Chem 8:415–459PubMedGoogle Scholar
  52. 52.
    Perrin F (1936) Brownian motion of an ellipsoid. II. Free rotation and depolarisation of fluorescence: Translation and diffusion of ellipsoidal molecules. J Phys Radium 7(1):1–11Google Scholar
  53. 53.
    Moerke NJ (2009) Fluorescence Polarization (FP) assays for monitoring peptide-protein or nucleic acid-protein binding. Curr Protoc Chem Biol 1(1):1–15PubMedGoogle Scholar
  54. 54.
    Lodge JM, Rettenmaier TJ, Wells JA, Pomerantz WC, Mapp AK (2014) FP tethering: a screening technique to rapidly identify compounds that disrupt protein–protein interactions. MedChemCommun 5(3):370–375Google Scholar
  55. 55.
    Lea WA, Simeonov A (2011) Fluorescence polarization assays in small molecule screening. Expert Opin Drug Discov 6(1):17–32PubMedPubMedCentralGoogle Scholar
  56. 56.
    Owicki JC (2000) Fluorescence polarization and anisotropy in high throughput screening: perspectives and primer. J Biomol Screen 5(5):297–306PubMedGoogle Scholar
  57. 57.
    Gribbon P, Sewing A (2003) Fluorescence readouts in HTS: no gain without pain? Drug Discov Today 8(22):1035–1043PubMedGoogle Scholar
  58. 58.
    Shoichet BK (2006) Screening in a spirit haunted world. Drug Discov Today 11(13–14):607–615PubMedPubMedCentralGoogle Scholar
  59. 59.
    Rush TS 3rd, Grant JA, Mosyak L, Nicholls A (2005) A shape-based 3-D scaffold hopping method and its application to a bacterial protein-protein interaction. J Med Chem 48(5):1489–1495PubMedGoogle Scholar
  60. 60.
    Zhuang C, Miao Z, Zhu L, Dong G, Guo Z, Wang S, Zhang Y, Wu Y, Yao J, Sheng C, Zhang W (2012) Discovery, synthesis, and biological evaluation of orally active pyrrolidone derivatives as novel inhibitors of p53-MDM2 protein-protein interaction. J Med Chem 55(22):9630–9642PubMedGoogle Scholar
  61. 61.
    Zhuang C, Miao Z, Wu Y, Guo Z, Li J, Yao J, Xing C, Sheng C, Zhang W (2014) Double-edged swords as cancer therapeutics: novel, orally active, small molecules simultaneously inhibit p53-MDM2 interaction and the NF-kappaB pathway. J Med Chem 57(3):567–577PubMedGoogle Scholar
  62. 62.
    Lu Y, Nikolovska-Coleska Z, Fang X, Gao W, Shangary S, Qiu S, Qin D, Wang S (2006) Discovery of a nanomolar inhibitor of the human murine double minute 2 (MDM2)-p53 interaction through an integrated, virtual database screening strategy. J Med Chem 49(13):3759–3762PubMedGoogle Scholar
  63. 63.
    Guo Z, Zhuang C, Zhu L, Zhang Y, Yao J, Dong G, Wang S, Liu Y, Chen H, Sheng C, Miao Z, Zhang W (2012) Structure-activity relationship and antitumor activity of thio-benzodiazepines as p53-MDM2 protein-protein interaction inhibitors. Eur J Med Chem 56:10–16PubMedGoogle Scholar
  64. 64.
    Zhuang C, Miao Z, Zhu L, Zhang Y, Guo Z, Yao J, Dong G, Wang S, Liu Y, Chen H, Sheng C, Zhang W (2011) Synthesis and biological evaluation of thio-benzodiazepines as novel small molecule inhibitors of the p53-MDM2 protein-protein interaction. Eur J Med Chem 46(11):5654–5661PubMedGoogle Scholar
  65. 65.
    Kiessling A, Sperl B, Hollis A, Eick D, Berg T (2006) Selective inhibition of c-Myc/Max dimerization and DNA binding by small molecules. Chem Biol 13(7):745–751PubMedGoogle Scholar
  66. 66.
    Degterev A, Lugovskoy A, Cardone M, Mulley B, Wagner G, Mitchison T, Yuan J (2001) Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL. Nat Cell Biol 3(2):173–182PubMedGoogle Scholar
  67. 67.
    Moerke NJ, Aktas H, Chen H, Cantel S, Reibarkh MY, Fahmy A, Gross JD, Degterev A, Yuan J, Chorev M, Halperin JA, Wagner G (2007) Small-molecule inhibition of the interaction between the translation initiation factors eIF4E and eIF4G. Cell 128(2):257–267PubMedGoogle Scholar
  68. 68.
    Förster T (1946) Th. Energiewanderung und Fluoreszenz. Naturwissenschaften 33:166–175Google Scholar
  69. 69.
    Wu P, Brand L (1994) Resonance energy transfer: methods and applications. Anal Biochem 218(1):1–13PubMedGoogle Scholar
  70. 70.
    Ma L, Yang F, Zheng J (2014) Application of fluorescence resonance energy transfer in protein studies. J Mol Struct 1077:87–100PubMedPubMedCentralGoogle Scholar
  71. 71.
    Schaap M, Hancock R, Wilderspin A, Wells G (2013) Development of a steady-state FRET-based assay to identify inhibitors of the Keap1-Nrf2 protein-protein interaction. Protein Sci 22(12):1812–1819PubMedPubMedCentralGoogle Scholar
  72. 72.
    Degorce F, Card A, Soh S, Trinquet E, Knapik GP, Xie B (2009) HTRF: a technology tailored for drug discovery—a review of theoretical aspects and recent applications. Curr Chem Genomics 3:22–32PubMedPubMedCentralGoogle Scholar
  73. 73.
    Du Y, Fu RW, Lou B, Zhao J, Qui M, Khuri FR, Fu H (2013) A time-resolved fluorescence resonance energy transfer assay for high-throughput screening of 14-3-3 protein-protein interaction inhibitors. Assay Drug Dev Technol 11(6):367–381PubMedPubMedCentralGoogle Scholar
  74. 74.
    Berg T, Cohen SB, Desharnais J, Sonderegger C, Maslyar DJ, Goldberg J, Boger DL, Vogt PK (2002) Small-molecule antagonists of Myc/Max dimerization inhibit Myc-induced transformation of chicken embryo fibroblasts. Proc Natl Acad Sci USA 99(6):3830–3835PubMedPubMedCentralGoogle Scholar
  75. 75.
    Mathis G (1995) Probing molecular interactions with homogeneous techniques based on rare earth cryptates and fluorescence energy transfer. Clin Chem 41(9):1391–1397PubMedGoogle Scholar
  76. 76.
    Arai R, Nakagawa H, Tsumoto K, Mahoney W, Kumagai I, Ueda H, Nagamune T (2001) Demonstration of a homogeneous noncompetitive immunoassay based on bioluminescence resonance energy transfer. Anal Biochem 289(1):77–81PubMedGoogle Scholar
  77. 77.
    Mazars A, Fahraeus R (2010) Using BRET to study chemical compound-induced disruptions of the p53-HDM2 interactions in live cells. Biotechnol J 5(4):377–384PubMedGoogle Scholar
  78. 78.
    Cryan LM, Habeshian KA, Caldwell TP, Morris MT, Ackroyd PC, Christensen KA, Rogers MS (2013) Identification of small molecules that inhibit the interaction of TEM8 with anthrax protective antigen using a FRET assay. J Biomol Screen 18(6):714–725PubMedGoogle Scholar
  79. 79.
    Guo L, Teng L (2015) YAP/TAZ for cancer therapy: opportunities and challenges (review). Int J Oncol 46(4):1444–1452PubMedGoogle Scholar
  80. 80.
    Glickman JF, Wu X, Mercuri R, Illy C, Bowen BR, He Y, Sills M (2002) A comparison of ALPHAScreen, TR-FRET, and TRF as assay methods for FXR nuclear receptors. J Biomol Screen 7(1):3–10PubMedGoogle Scholar
  81. 81.
    Schorpp K, Rothenaigner I, Salmina E, Reinshagen J, Low T, Brenke JK, Gopalakrishnan J, Tetko IV, Gul S, Hadian K (2014) Identification of small-molecule frequent hitters from AlphaScreen high-throughput screens. J Biomol Screen 19(5):715–726PubMedPubMedCentralGoogle Scholar
  82. 82.
    Hou Y, McGuinness DE, Prongay AJ, Feld B, Ingravallo P, Ogert RA, Lunn CA, Howe JA (2008) Screening for antiviral inhibitors of the HIV integrase-LEDGF/p75 interaction using the AlphaScreen luminescent proximity assay. J Biomol Screen 13(5):406–414PubMedGoogle Scholar
  83. 83.
    Zimmermann G, Papke B, Ismail S, Vartak N, Chandra A, Hoffmann M, Hahn SA, Triola G, Wittinghofer A, Bastiaens PI, Waldmann H (2013) Small molecule inhibition of the KRAS-PDEdelta interaction impairs oncogenic KRAS signalling. Nature 497(7451):638–642PubMedGoogle Scholar
  84. 84.
    Whitby RJ, Dixon S, Maloney PR, Delerive P, Goodwin BJ, Parks DJ, Willson TM (2006) Identification of small molecule agonists of the orphan nuclear receptors liver receptor homolog-1 and steroidogenic factor-1. J Med Chem 49(23):6652–6655PubMedGoogle Scholar
  85. 85.
    Cheng K, Wang X, Zhang S, Yin H (2012) Discovery of small-molecule inhibitors of the TLR1/TLR2 complex. Angew Chem Int Ed Engl 51(49):12246–12249PubMedPubMedCentralGoogle Scholar
  86. 86.
    Goudreau N, Cameron DR, Deziel R, Hache B, Jakalian A, Malenfant E, Naud J, Ogilvie WW, O’Meara J, White PW, Yoakim C (2007) Optimization and determination of the absolute configuration of a series of potent inhibitors of human papillomavirus type-11 E1-E2 protein-protein interaction: a combined medicinal chemistry, NMR and computational chemistry approach. Bioorg Med Chem 15(7):2690–2700PubMedGoogle Scholar
  87. 87.
    Yoakim C, Ogilvie WW, Goudreau N, Naud J, Hache B, O’Meara JA, Cordingley MG, Archambault J, White PW (2003) Discovery of the first series of inhibitors of human papillomavirus type 11: inhibition of the assembly of the E1-E2-Origin DNA complex. Bioorg Med Chem Lett 13(15):2539–2541PubMedGoogle Scholar
  88. 88.
    Arnold LA, Estebanez-Perpina E, Togashi M, Jouravel N, Shelat A, McReynolds AC, Mar E, Nguyen P, Baxter JD, Fletterick RJ, Webb P, Guy RK (2005) Discovery of small molecule inhibitors of the interaction of the thyroid hormone receptor with transcriptional coregulators. J Biol Chem 280(52):43048–43055PubMedGoogle Scholar
  89. 89.
    Grembecka J, He S, Shi A, Purohit T, Muntean AG, Sorenson RJ, Showalter HD, Murai MJ, Belcher AM, Hartley T, Hess JL, Cierpicki T (2012) Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nat Chem Biol 8(3):277–284PubMedPubMedCentralGoogle Scholar
  90. 90.
    He S, Senter TJ, Pollock J, Han C, Upadhyay SK, Purohit T, Gogliotti RD, Lindsley CW, Cierpicki T, Stauffer SR, Grembecka J (2014) High-affinity small-molecule inhibitors of the menin-mixed lineage leukemia (MLL) interaction closely mimic a natural protein-protein interaction. J Med Chem 57(4):1543–1556PubMedPubMedCentralGoogle Scholar
  91. 91.
    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):909–912PubMedGoogle Scholar
  92. 92.
    Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, Pavletich NP (1996) Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 274(5289):948–953PubMedGoogle Scholar
  93. 93.
    Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303(5659):844–848PubMedGoogle Scholar
  94. 94.
    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):466–469PubMedPubMedCentralGoogle Scholar
  95. 95.
    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):2587–2597PubMedGoogle Scholar
  96. 96.
    Ray-Coquard I, Blay JY, Italiano A, Le Cesne A, Penel N, Zhi J, Heil F, Rueger R, Graves B, Ding M, Geho D, Middleton SA, Vassilev LT, Nichols GL, Bui BN (2012) Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol 13(11):1133–1140PubMedGoogle Scholar
  97. 97.
    Koblish HK, Zhao S, Franks CF, Donatelli RR, Tominovich RM, LaFrance LV, Leonard KA, Gushue JM, Parks DJ, Calvo RR, Milkiewicz KL, Marugan JJ, Raboisson P, Cummings MD, Grasberger BL, Johnson DL, Lu T, Molloy CJ, Maroney AC (2006) Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo. Mol Cancer Ther 5(1):160–169PubMedGoogle Scholar
  98. 98.
    Baker NM, Der CJ (2013) Cancer: drug for an ‘undruggable’ protein. Nature 497(7451):577–578PubMedPubMedCentralGoogle Scholar
  99. 99.
    Zimmermann G, Schultz-Fademrecht C, Kuchler P, Murarka S, Ismail S, Triola G, Nussbaumer P, Wittinghofer A, Waldmann H (2014) Structure guided design and kinetic analysis of highly potent benzimidazole inhibitors targeting the PDEdelta prenyl binding site. J Med Chem 57(12):5435–5448PubMedGoogle Scholar
  100. 100.
    Papke B, Murarka S, Vogel HA, Martin-Gago P, Kovacevic M, Truxius DC, Fansa EK, Ismail S, Zimmermann G, Heinelt K, Schultz-Fademrecht C, Al Saabi A, Baumann M, Nussbaumer P, Wittinghofer A, Waldmann H, Bastiaens PI (2016) Identification of pyrazolopyridazinones as PDEdelta inhibitors. Nat Commun 7:11360PubMedPubMedCentralGoogle Scholar
  101. 101.
    Martín-Gago P, Fansa EK, Klein CH, Murarka S, Janning P, Schürmann M, Metz M, Ismail S, Schultz-Fademrecht C, Baumann M, Bastiaens PIH, Wittinghofer A, Waldmann H (2017) A PDE6δ-KRas inhibitor chemotype with up to seven H-bonds and picomolar affinity that prevents efficient inhibitor release by Arl2. Angew Chem Int Ed Engl 56(9):2423–2428PubMedGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of Medicinal Chemistry, School of PharmacySecond Military Medical UniversityShanghaiChina

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