1932

Abstract

The central dogma of molecular biology, that DNA is transcribed into RNA and RNA translated into protein, was coined in the early days of modern biology. Back in the 1950s and 1960s, bacterial genetics first opened the way toward understanding life as the genetically encoded interaction of macromolecules. As molecular biology progressed and our knowledge of gene control deepened, it became increasingly clear that expression relied on many more levels of regulation. In the process of dissecting mechanisms of gene expression, specific small-molecule inhibitors played an important role and became valuable tools of investigation. Small molecules offer significant advantages over genetic tools, as they allow inhibiting a process at any desired time point, whereas mutating or altering the gene of an important regulator would likely result in a dead organism. With the advent of modern sequencing technology, it has become possible to monitor global cellular effects of small-molecule treatment and thereby overcome the limitations of classical biochemistry, which usually looks at a biological system in isolation. This review focuses on several molecules, especially natural products, that have played an important role in dissecting gene expression and have opened up new fields of investigation as well as clinical venues for disease treatment.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-biochem-060614-033923
2018-06-20
2024-06-21
Loading full text...

Full text loading...

/deliver/fulltext/biochem/87/1/annurev-biochem-060614-033923.html?itemId=/content/journals/10.1146/annurev-biochem-060614-033923&mimeType=html&fmt=ahah

Literature Cited

  1. 1.  Theis N, Lerdau M 2003. The evolution of function in plant secondary metabolites. Int. J. Plant Sci. 164:S93–102
    [Google Scholar]
  2. 2.  Newman DJ, Cragg GM 2012. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J. Nat. Prod. 75:311–35
    [Google Scholar]
  3. 3.  Li JWH, Vederas JC 2009. Drug discovery and natural products: end of an era or an endless frontier?. Science 325:161–65
    [Google Scholar]
  4. 4.  Koehn FE, Carter GT 2005. The evolving role of natural products in drug discovery. Nat. Rev. Drug Discov. 4:206–20
    [Google Scholar]
  5. 5.  Harvey AL, Edrada-Ebel R, Quinn RJ 2015. The re-emergence of natural products for drug discovery in the genomics era. Nat. Rev. Drug Discov. 14:111–29
    [Google Scholar]
  6. 6.  Stent GS. 1968. That was the molecular biology that was. Science 160:390–95
    [Google Scholar]
  7. 7.  Ahlquist P. 2002. RNA-dependent RNA polymerases, viruses, and RNA silencing. Science 296:1270–73
    [Google Scholar]
  8. 8.  Filipowicz W, Jaskiewicz L, Kolb FA, Pillai RS 2005. Post-transcriptional gene silencing by siRNAs and miRNAs. Curr. Opin. Struct. Biol. 15:331–41
    [Google Scholar]
  9. 9.  Chi P, Allis CD, Wang GG 2010. Covalent histone modifications—miswritten, misinterpreted and mis-erased in human cancers. Nat. Rev. Cancer 10:457–69
    [Google Scholar]
  10. 10.  Yoshida M, Kudo N, Kosono S, Ito A 2017. Chemical and structural biology of protein lysine deacetylases. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 93:297–321
    [Google Scholar]
  11. 11.  Lemon B, Tjian R 2000. Orchestrated response: a symphony of transcription factors for gene control. Genes Dev 14:2551–69
    [Google Scholar]
  12. 12.  Darnell JE. 2002. Transcription factors as targets for cancer therapy. Nat. Rev. Cancer 2:740–49
    [Google Scholar]
  13. 13.  Bork PM, Schmitz ML, Kuhnt M, Escher C, Heinrich M 1997. Sesquiterpene lactone containing Mexican Indian medicinal plants and pure sesquiterpene lactones as potent inhibitors of transcription factor NF-κB. FEBS Lett 402:85–90
    [Google Scholar]
  14. 14.  Gilmore TD. 2006. Introduction to NF-κB: players, pathways, perspectives. Oncogene 25:6680–84
    [Google Scholar]
  15. 15.  Garcia-Pineres AJ, Castro V, Mora G, Schmidt TJ, Strunck E et al. 2001. Cysteine 38 in p65/NF-κB plays a crucial role in DNA binding inhibition by sesquiterpene lactones. J. Biol. Chem. 276:39713–20
    [Google Scholar]
  16. 16.  Kwok BH, Koh B, Ndubuisi MI, Elofsson M, Crews CM 2001. The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IκB kinase. Chem. Biol. 8:759–66
    [Google Scholar]
  17. 17.  Hehner SP, Hofmann TG, Droge W, Schmitz ML 1999. The antiinflammatory sesquiterpene lactone parthenolide inhibits NF-κB by targeting the IκB kinase complex. J. Immunol. 163:5617–23
    [Google Scholar]
  18. 18.  Guzman ML, Rossi RM, Neelakantan S, Li X, Corbett CA et al. 2007. An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells. Blood 110:4427–35
    [Google Scholar]
  19. 19.  Duan D, Zhang J, Yao J, Liu Y, Fang J 2016. Targeting thioredoxin reductase by parthenolide contributes to inducing apoptosis of HeLa cells. J. Biol. Chem. 291:10021–31
    [Google Scholar]
  20. 20.  Ghantous A, Sinjab A, Herceg Z, Darwiche N 2013. Parthenolide: from plant shoots to cancer roots. Drug Discov. Today 18:894–905
    [Google Scholar]
  21. 21.  Reich E, Franklin RM, Shatkin AJ, Tatum EL 1961. Effect of actinomycin D on cellular nucleic acid synthesis and virus production. Science 134:556–57
    [Google Scholar]
  22. 22.  Goldberg IH, Rabinowitz M, Reich E 1962. Basis of actinomycin action. I. DNA binding and inhibition of RNA-polymerase synthetic reactions by actinomycin. PNAS 48:2094–101
    [Google Scholar]
  23. 23.  Perry RP, Kelley DE 1970. Inhibition of RNA synthesis by actinomycin D: characteristic dose-response of different RNA species. J. Cell Physiol. 76:127–39
    [Google Scholar]
  24. 24.  Wadkins RM, Vladu B, Tung CS 1998. Actinomycin D binds to metastable hairpins in single-stranded DNA. Biochemistry 37:11915–23
    [Google Scholar]
  25. 25.  Rill RL, Hecker KH 1996. Sequence-specific actinomycin D binding to single-stranded DNA inhibits HIV reverse transcriptase and other polymerases. Biochemistry 35:3525–33
    [Google Scholar]
  26. 26.  Kamitori S, Takusagawa F 1994. Multiple binding modes of anticancer drug actinomycin D: X-ray, molecular modeling, and spectroscopic studies of d(GAAGCTTC)2-actinomycin D complexes and its host DNA. J. Am. Chem. Soc. 116:4154–65
    [Google Scholar]
  27. 27.  Hou MH, Robinson H, Gao YG, Wang AH 2002. Crystal structure of actinomycin D bound to the CTG triplet repeat sequences linked to neurological diseases. Nucleic Acids Res 30:4910–17
    [Google Scholar]
  28. 28.  Maier JG, Harshaw WG 1967. Treatment and prognosis in Wilms’ tumor. A study of 51 cases with special reference to role of actinomycin D. Cancer 20:96–102
    [Google Scholar]
  29. 29.  Schultz LD, Hall BD 1976. Transcription in yeast: α-amanitin sensitivity and other properties which distinguish between RNA polymerases I and III. PNAS 73:1029–33
    [Google Scholar]
  30. 30.  Nguyen VT, Giannoni F, Dubois MF, Seo SJ, Vigneron M et al. 1996. In vivo degradation of RNA polymerase II largest subunit triggered by α-amanitin. Nucleic Acids Res 24:2924–29
    [Google Scholar]
  31. 31.  Brueckner F, Cramer P 2008. Structural basis of transcription inhibition by α-amanitin and implications for RNA polymerase II translocation. Nat. Struct. Mol. Biol. 15:811–18
    [Google Scholar]
  32. 32.  Chao SH, Fujinaga K, Marion JE, Taube R, Sausville EA et al. 2000. Flavopiridol inhibits P-TEFb and blocks HIV-1 replication. J. Biol. Chem. 275:28345–48
    [Google Scholar]
  33. 33.  Chao SH, Price DH 2001. Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. J. Biol. Chem. 276:31793–99
    [Google Scholar]
  34. 34.  He QL, Titov DV, Li J, Tan M, Ye Z et al. 2015. Covalent modification of a cysteine residue in the XPB subunit of the general transcription factor TFIIH through single epoxide cleavage of the transcription inhibitor triptolide. Angew. Chem. Int. Ed. Engl. 54:1859–63
    [Google Scholar]
  35. 35.  Titov DV, Gilman B, He QL, Bhat S, Low WK et al. 2011. XPB, a subunit of TFIIH, is a target of the natural product triptolide. Nat. Chem. Biol. 7:182–88
    [Google Scholar]
  36. 36.  Jenuwein T, Allis CD 2001. Translating the histone code. Science 293:1074–80
    [Google Scholar]
  37. 37.  Yang X, Lay F, Han H, Jones PA 2010. Targeting DNA methylation for epigenetic therapy. Trends Pharmacol. Sci. 31:536–46
    [Google Scholar]
  38. 38.  Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H et al. 2009. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324:930–35
    [Google Scholar]
  39. 39.  Ghoshal K, Datta J, Majumder S, Bai S, Kutay H et al. 2005. 5-Aza-deoxycytidine induces selective degradation of DNA methyltransferase 1 by a proteasomal pathway that requires the KEN box, bromo-adjacent homology domain, and nuclear localization signal. Mol. Cell. Biol. 25:4727–41
    [Google Scholar]
  40. 40.  Datta J, Ghoshal K, Denny WA, Gamage SA, Brooke DG et al. 2009. A new class of quinoline-based DNA hypomethylating agents reactivates tumor suppressor genes by blocking DNA methyltransferase 1 activity and inducing its degradation. Cancer Res 69:4277–85
    [Google Scholar]
  41. 41.  Patel K, Dickson J, Din S, Macleod K, Jodrell D, Ramsahoye B 2010. Targeting of 5-aza-2′-deoxycytidine residues by chromatin-associated DNMT1 induces proteasomal degradation of the free enzyme. Nucleic Acids Res 38:4313–24
    [Google Scholar]
  42. 42.  Erdmann A, Halby L, Fahy J, Arimondo PB 2015. Targeting DNA methylation with small molecules: What's next?. J. Med. Chem. 58:2569–83
    [Google Scholar]
  43. 43.  Flotho C, Claus R, Batz C, Schneider M, Sandrock I et al. 2009. The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia 23:1019–28
    [Google Scholar]
  44. 44.  Rilova E, Erdmann A, Gros C, Masson V, Aussagues Y et al. 2014. Design, synthesis and biological evaluation of 4-amino-N-(4-aminophenyl)benzamide analogues of quinoline-based SGI-1027 as inhibitors of DNA methylation. Chem. Med. Chem. 9:590–601
    [Google Scholar]
  45. 45.  Allfrey VG, Faulkner R, Mirsky AE 1964. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. PNAS 51:786–94
    [Google Scholar]
  46. 46.  Riggs MG, Whittaker RG, Neumann JR, Ingram VM 1977. n-Butyrate causes histone modification in HeLa and Friend erythroleukaemia cells. Nature 268:462–64
    [Google Scholar]
  47. 47.  Yoshida M, Kijima M, Akita M, Beppu T 1990. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J. Biol. Chem. 265:17174–79
    [Google Scholar]
  48. 48.  Richon VM, Webb Y, Merger R, Sheppard T, Jursic B et al. 1996. Second generation hybrid polar compounds are potent inducers of transformed cell differentiation. PNAS 93:5705–8
    [Google Scholar]
  49. 49.  Taunton J, Hassig CA, Schreiber SL 1996. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272:408–11
    [Google Scholar]
  50. 50.  Kijima M, Yoshida M, Sugita K, Horinouchi S, Beppu T 1993. Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase. J. Biol. Chem. 268:22429–35
    [Google Scholar]
  51. 51.  Yoshida M, Horinouchi S, Beppu T 1995. Trichostatin A and trapoxin: novel chemical probes for the role of histone acetylation in chromatin structure and function. Bioessays 17:423–30
    [Google Scholar]
  52. 52.  Darkin-Rattray SJ, Gurnett AM, Myers RW, Dulski PM, Crumley TM et al. 1996. Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase. PNAS 93:13143–47
    [Google Scholar]
  53. 53.  Liesch JM, Sweeley CC, Staffeld GD, Anderson MS, Weber DJ, Scheffer RP 1982. Structure of HC-toxin, a cyclic tetrapeptide from Helminthosporium carbonum. Tetrahedron 38:45–48
    [Google Scholar]
  54. 54.  Closse A, Huguenin R 1974. Isolation and structural clarification of chlamydocin. Helv. Chim. Acta 57:533–45
    [Google Scholar]
  55. 55.  Furumai R, Matsuyama A, Kobashi N, Lee KH, Nishiyama M et al. 2002. FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases. Cancer Res 62:4916–21
    [Google Scholar]
  56. 56.  Komatsu Y, Tomizaki KY, Tsukamoto M, Kato T, Nishino N et al. 2001. Cyclic hydroxamic-acid-containing peptide 31, a potent synthetic histone deacetylase inhibitor with antitumor activity. Cancer Res 61:4459–66
    [Google Scholar]
  57. 57.  Furumai R, Komatsu Y, Nishino N, Khochbin S, Yoshida M, Horinouchi S 2001. Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin. PNAS 98:87–92
    [Google Scholar]
  58. 58.  Hai Y, Christianson DW 2016. Histone deacetylase 6 structure and molecular basis of catalysis and inhibition. Nat. Chem. Biol. 12:741–47
    [Google Scholar]
  59. 59.  Miyake Y, Keusch JJ, Wang L, Saito M, Hess D et al. 2016. Structural insights into HDAC6 tubulin deacetylation and its selective inhibition. Nat. Chem. Biol. 12:748–54
    [Google Scholar]
  60. 60.  Kiernan R, Bres V, Ng RW, Coudart MP, El Messaoudi S et al. 2003. Post-activation turn-off of NF-κB-dependent transcription is regulated by acetylation of p65. J. Biol. Chem. 278:2758–66
    [Google Scholar]
  61. 61.  Chen L, Fischle W, Verdin E, Greene WC 2001. Duration of nuclear NF-κB action regulated by reversible acetylation. Science 293:1653–57
    [Google Scholar]
  62. 62.  Bheda P, Jing H, Wolberger C, Lin H 2016. The substrate specificity of sirtuins. Annu. Rev. Biochem. 85:405–29
    [Google Scholar]
  63. 63.  North BJ, Verdin E 2007. Interphase nucleo-cytoplasmic shuttling and localization of SIRT2 during mitosis. PLOS ONE 2:e784
    [Google Scholar]
  64. 64.  Napper AD, Hixon J, McDonagh T, Keavey K, Pons JF et al. 2005. Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1. J. Med. Chem. 48:8045–54
    [Google Scholar]
  65. 65.  Rumpf T, Schiedel M, Karaman B, Roessler C, North BJ et al. 2015. Selective Sirt2 inhibition by ligand-induced rearrangement of the active site. Nat. Commun. 6:6263
    [Google Scholar]
  66. 66.  Schuetz A, Min J, Antoshenko T, Wang CL, Allali-Hassani A et al. 2007. Structural basis of inhibition of the human NAD+-dependent deacetylase SIRT5 by suramin. Structure 15:377–89
    [Google Scholar]
  67. 67.  Communi D, Robaye B, Boeynaems JM 1999. Pharmacological characterization of the human P2Y11 receptor. Br. J. Pharmacol. 128:1199–206
    [Google Scholar]
  68. 68.  Kovacs JJ, Murphy PJ, Gaillard S, Zhao X, Wu JT et al. 2005. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol. Cell 18:601–7
    [Google Scholar]
  69. 69.  Tan M, Luo H, Lee S, Jin F, Yang JS et al. 2011. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146:1016–28
    [Google Scholar]
  70. 70.  Chen Y, Sprung R, Tang Y, Ball H, Sangras B et al. 2007. Lysine propionylation and butyrylation are novel post-translational modifications in histones. Mol. Cell Proteom. 6:812–19
    [Google Scholar]
  71. 71.  Smith BC, Denu JM 2007. Acetyl-lysine analog peptides as mechanistic probes of protein deacetylases. J. Biol. Chem. 282:37256–65
    [Google Scholar]
  72. 72.  Peng C, Lu Z, Xie Z, Cheng Z, Chen Y et al. 2011. The first identification of lysine malonylation substrates and its regulatory enzyme. Mol. Cell Proteom. 10:M111.012658
    [Google Scholar]
  73. 73.  Du J, Zhou Y, Su X, Yu JJ, Khan S et al. 2011. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 334:806–9
    [Google Scholar]
  74. 74.  Balasubramanyam K, Altaf M, Varier RA, Swaminathan V, Ravindran A et al. 2004. Polyisoprenylated benzophenone, garcinol, a natural histone acetyltransferase inhibitor, represses chromatin transcription and alters global gene expression. J. Biol. Chem. 279:33716–26
    [Google Scholar]
  75. 75.  Balasubramanyam K, Varier RA, Altaf M, Swaminathan V, Siddappa NB et al. 2004. Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. J. Biol. Chem. 279:51163–71
    [Google Scholar]
  76. 76.  Egawa N, Kitaoka S, Tsukita K, Naitoh M, Takahashi K et al. 2012. Drug screening for ALS using patient-specific induced pluripotent stem cells. Sci. Transl. Med. 4:145ra04
    [Google Scholar]
  77. 77.  Fukuda I, Ito A, Hirai G, Nishimura S, Kawasaki H et al. 2009. Ginkgolic acid inhibits protein SUMOylation by blocking formation of the E1-SUMO intermediate. Chem. Biol. 16:133–40
    [Google Scholar]
  78. 78.  Bowers EM, Yan G, Mukherjee C, Orry A, Wang L et al. 2010. Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor. Chem. Biol. 17:471–82
    [Google Scholar]
  79. 79.  Yan G, Eller MS, Elm C, Larocca CA, Ryu B et al. 2013. Selective inhibition of p300 HAT blocks cell cycle progression, induces cellular senescence, and inhibits the DNA damage response in melanoma cells. J. Invest. Dermatol. 133:2444–52
    [Google Scholar]
  80. 80.  Oike T, Komachi M, Ogiwara H, Amornwichet N, Saitoh Y et al. 2014. C646, a selective small molecule inhibitor of histone acetyltransferase p300, radiosensitizes lung cancer cells by enhancing mitotic catastrophe. Radiother. Oncol. 111:222–27
    [Google Scholar]
  81. 81.  Nicodeme E, Jeffrey KL, Schaefer U, Beinke S, Dewell S et al. 2010. Suppression of inflammation by a synthetic histone mimic. Nature 468:1119–23
    [Google Scholar]
  82. 82.  Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB et al. 2010. Selective inhibition of BET bromodomains. Nature 468:1067–73
    [Google Scholar]
  83. 83.  Bhadury J, Nilsson LM, Muralidharan SV, Green LC, Li Z et al. 2014. BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma. PNAS 111:E2721–30
    [Google Scholar]
  84. 84.  Ito T, Umehara T, Sasaki K, Nakamura Y, Nishino N et al. 2011. Real-time imaging of histone H4K12-specific acetylation determines the modes of action of histone deacetylase and bromodomain inhibitors. Chem. Biol. 18:495–507
    [Google Scholar]
  85. 85.  Nakaoka S, Sasaki K, Ito A, Nakao Y, Yoshida M 2016. A genetically encoded FRET probe to detect intranucleosomal histone H3K9 or H3K14 acetylation using BRD4, a BET family member. ACS Chem. Biol. 11:729–33
    [Google Scholar]
  86. 86.  Tachibana M, Sugimoto K, Fukushima T, Shinkai Y 2001. Set domain-containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone H3. J. Biol. Chem. 276:25309–17
    [Google Scholar]
  87. 87.  Casciello F, Windloch K, Gannon F, Lee JS 2015. Functional role of G9a histone methyltransferase in cancer. Front. Immunol. 6:487
    [Google Scholar]
  88. 88.  Greiner D, Bonaldi T, Eskeland R, Roemer E, Imhof A 2005. Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3-9. Nat. Chem. Biol. 1:143–45
    [Google Scholar]
  89. 89.  Cherblanc FL, Chapman KL, Brown R, Fuchter MJ 2013. Chaetocin is a nonspecific inhibitor of histone lysine methyltransferases. Nat. Chem. Biol. 9:136–37
    [Google Scholar]
  90. 90.  Cherblanc FL, Chapman KL, Reid J, Borg AJ, Sundriyal S et al. 2013. On the histone lysine methyltransferase activity of fungal metabolite chaetocin. J. Med. Chem. 56:8616–25
    [Google Scholar]
  91. 91.  Fujishiro S, Dodo K, Iwasa E, Teng Y, Sohtome Y et al. 2013. Epidithiodiketopiperazine as a pharmacophore for protein lysine methyltransferase G9a inhibitors: reducing cytotoxicity by structural simplification. Bioorg. Med. Chem. Lett. 23:733–36
    [Google Scholar]
  92. 92.  Kubicek S, O'Sullivan RJ, August EM, Hickey ER, Zhang Q et al. 2007. Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol. Cell 25:473–81
    [Google Scholar]
  93. 93.  Liu F, Chen X, Allali-Hassani A, Quinn AM, Wigle TJ et al. 2010. Protein lysine methyltransferase G9a inhibitors: design, synthesis, and structure activity relationships of 2,4-diamino-7-aminoalkoxy-quinazolines. J. Med. Chem. 53:5844–57
    [Google Scholar]
  94. 94.  Kim KH, Roberts CW 2016. Targeting EZH2 in cancer. Nat. Med. 22:128–34
    [Google Scholar]
  95. 95.  McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C et al. 2012. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492:108–12
    [Google Scholar]
  96. 96.  Knutson SK, Warholic NM, Wigle TJ, Klaus CR, Allain CJ et al. 2013. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. PNAS 110:7922–27
    [Google Scholar]
  97. 97.  Daigle SR, Olhava EJ, Therkelsen CA, Basavapathruni A, Jin L et al. 2013. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood 122:1017–25
    [Google Scholar]
  98. 98.  Stein EM, Garcia-Manero G, Rizzieri DA, Tibes R, Berdeja JG et al. 2015. A phase 1 study of the DOT1L inhibitor, pinometostat (EPZ-5676), in adults with relapsed or refractory leukemia: safety, clinical activity, exposure and target inhibition. Blood 126:2547
    [Google Scholar]
  99. 99.  Casper A, Van Doren M 2006. The control of sexual identity in the Drosophila germline. Development 133:2783–91
    [Google Scholar]
  100. 100.  Harper SJ, Bates DO 2008. VEGF-A splicing: the key to anti-angiogenic therapeutics?. Nat. Rev. Cancer 8:880–87
    [Google Scholar]
  101. 101.  Kaida D, Motoyoshi H, Tashiro E, Nojima T, Hagiwara M et al. 2007. Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA. Nat. Chem. Biol. 3:576–83
    [Google Scholar]
  102. 102.  Corrionero A, Minana B, Valcarcel J 2011. Reduced fidelity of branch point recognition and alternative splicing induced by the anti-tumor drug spliceostatin A. Genes Dev 25:445–59
    [Google Scholar]
  103. 103.  Kotake Y, Sagane K, Owa T, Mimori-Kiyosue Y, Shimizu H et al. 2007. Splicing factor SF3b as a target of the antitumor natural product pladienolide. Nat. Chem. Biol. 3:570–75
    [Google Scholar]
  104. 104.  Furumai R, Uchida K, Komi Y, Yoneyama M, Ishigami K et al. 2010. Spliceostatin A blocks angiogenesis by inhibiting global gene expression including VEGF. Cancer Sci 101:2483–89
    [Google Scholar]
  105. 105.  Khan K, Schneider-Poetsch T, Ishfaq M, Ito A, Yoshimoto R et al. 2014. Splicing inhibition induces gene expression through canonical NF-κB pathway and extracellular signal-related kinase activation. FEBS Lett 588:1053–57
    [Google Scholar]
  106. 106.  Koga M, Satoh T, Takasaki I, Kawamura Y, Yoshida M, Kaida D 2014. U2 snRNP is required for expression of the 3′ end of genes. PLOS ONE 9:e98015
    [Google Scholar]
  107. 107.  Kim S, Kim H, Fong N, Erickson B, Bentley DL 2011. Pre-mRNA splicing is a determinant of histone H3K36 methylation. PNAS 108:13564–69
    [Google Scholar]
  108. 108.  Folco EG, Coil KE, Reed R 2011. The anti-tumor drug E7107 reveals an essential role for SF3b in remodeling U2 snRNP to expose the branch point-binding region. Genes Dev 25:440–44
    [Google Scholar]
  109. 109.  O'Brien K, Matlin AJ, Lowell AM, Moore MJ 2008. The biflavonoid isoginkgetin is a general inhibitor of pre-mRNA splicing. J. Biol. Chem. 283:33147–54
    [Google Scholar]
  110. 110.  Nishida A, Kataoka N, Takeshima Y, Yagi M, Awano H et al. 2011. Chemical treatment enhances skipping of a mutated exon in the dystrophin gene. Nat. Commun. 2:308
    [Google Scholar]
  111. 111.  Sakuma M, Iida K, Hagiwara M 2015. Deciphering targeting rules of splicing modulator compounds: case of TG003. BMC Mol. Biol. 16:16
    [Google Scholar]
  112. 112.  Palacino J, Swalley SE, Song C, Cheung AK, Shu L et al. 2015. SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice. Nat. Chem. Biol. 11:511–17
    [Google Scholar]
  113. 113.  Hua Y, Sahashi K, Hung G, Rigo F, Passini MA et al. 2010. Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev 24:1634–44
    [Google Scholar]
  114. 114.  Wan L, Dreyfuss G 2017. Splicing-correcting therapy for SMA. Cell 170:5
    [Google Scholar]
  115. 115.  Nguyen KT, Holloway MP, Altura RA 2012. The CRM1 nuclear export protein in normal development and disease. Int. J. Biochem. Mol. Biol. 3:137–51
    [Google Scholar]
  116. 116.  Kudo N, Khochbin S, Nishi K, Kitano K, Yanagida M et al. 1997. Molecular cloning and cell cycle-dependent expression of mammalian CRM1, a protein involved in nuclear export of proteins. J. Biol. Chem. 272:29742–51
    [Google Scholar]
  117. 117.  Fornerod M, Ohno M, Yoshida M, Mattaj IW 1997. CRM1 is an export receptor for leucine-rich nuclear export signals. Cell 90:1051–60
    [Google Scholar]
  118. 118.  Fukuda M, Asano S, Nakamura T, Adachi M, Yoshida M et al. 1997. CRM1 is responsible for intracellular transport mediated by the nuclear export signal. Nature 390:308–11
    [Google Scholar]
  119. 119.  Culjkovic-Kraljacic B, Borden KL 2013. Aiding and abetting cancer: mRNA export and the nuclear pore. Trends Cell Biol 23:328–35
    [Google Scholar]
  120. 120.  Gallouzi IE, Steitz JA 2001. Delineation of mRNA export pathways by the use of cell-permeable peptides. Science 294:1895–901
    [Google Scholar]
  121. 121.  Culjkovic B, Borden KL 2009. Understanding and targeting the eukaryotic translation initiation factor eIF4E in head and neck cancer. J. Oncol. 2009:981679
    [Google Scholar]
  122. 122.  Dickmanns A, Monecke T, Ficner R 2015. Structural basis of targeting the exportin CRM1 in cancer. Cells 4:538–68
    [Google Scholar]
  123. 123.  Sun Q, Carrasco YP, Hu Y, Guo X, Mirzaei H et al. 2013. Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1. PNAS 110:1303–8
    [Google Scholar]
  124. 124.  Kudo N, Wolff B, Sekimoto T, Schreiner EP, Yoneda Y et al. 1998. Leptomycin B inhibition of signal-mediated nuclear export by direct binding to CRM1. Exp. Cell Res. 242:540–47
    [Google Scholar]
  125. 125.  Newlands ES, Rustin GJ, Brampton MH 1996. Phase I trial of elactocin. Br. J. Cancer 74:648–49
    [Google Scholar]
  126. 126.  Etchin J, Montero J, Berezovskaya A, Le BT, Kentsis A et al. 2016. Activity of a selective inhibitor of nuclear export, selinexor (KPT-330), against AML-initiating cells engrafted into immunosuppressed NSG mice. Leukemia 30:190–99
    [Google Scholar]
  127. 127.  Kalid O, Toledo Warshaviak D, Shechter S, Sherman W, Shacham S 2012. Consensus Induced Fit Docking (cIFD): methodology, validation, and application to the discovery of novel Crm1 inhibitors. J. Comput. Aided Mol. Des. 26:1217–28
    [Google Scholar]
  128. 128.  Kim J, McMillan E, Kim HS, Venkateswaran N, Makkar G et al. 2016. XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer. Nature 538:114–17
    [Google Scholar]
  129. 129.  Singh G, Kucukural A, Cenik C, Leszyk JD, Shaffer SA et al. 2012. The cellular EJC interactome reveals higher-order mRNP structure and an EJC-SR protein nexus. Cell 151:750–64
    [Google Scholar]
  130. 130.  Kashima I, Yamashita A, Izumi N, Kataoka N, Morishita R et al. 2006. Binding of a novel SMG-1-Upf1-eRF1-eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsense-mediated mRNA decay. Genes Dev 20:355–67
    [Google Scholar]
  131. 131.  Durand S, Cougot N, Mahuteau-Betzer F, Nguyen CH, Grierson DS et al. 2007. Inhibition of nonsense-mediated mRNA decay (NMD) by a new chemical molecule reveals the dynamic of NMD factors in P-bodies. J. Cell Biol. 178:1145–60
    [Google Scholar]
  132. 132.  Ishigaki Y, Li X, Serin G, Maquat LE 2001. Evidence for a pioneer round of mRNA translation: mRNAs subject to nonsense-mediated decay in mammalian cells are bound by CBP80 and CBP20. Cell 106:607–17
    [Google Scholar]
  133. 133.  Miyamoto Y, Machida K, Mizunuma M, Emoto Y, Sato N et al. 2002. Identification of Saccharomyces cerevisiae isoleucyl-tRNA synthetase as a target of the G1-specific inhibitor reveromycin A. J. Biol. Chem. 277:28810–14
    [Google Scholar]
  134. 134.  Osada H. 2016. Chemical and biological studies of reveromycin A. J. Antibiot. 69:723–30
    [Google Scholar]
  135. 135.  Keller TL, Zocco D, Sundrud MS, Hendrick M, Edenius M et al. 2012. Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. Nat. Chem. Biol. 8:311–17
    [Google Scholar]
  136. 136.  Rock FL, Mao W, Yaremchuk A, Tukalo M, Crepin T et al. 2007. An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site. Science 316:1759–61
    [Google Scholar]
  137. 137.  Fonseca BD, Smith EM, Yelle N, Alain T, Bushell M, Pause A 2014. The ever-evolving role of mTOR in translation. Semin. Cell Dev. Biol. 36:102–12
    [Google Scholar]
  138. 138.  Low WK, Dang Y, Schneider-Poetsch T, Shi Z, Choi NS et al. 2005. Inhibition of eukaryotic translation initiation by the marine natural product pateamine A. Mol. Cell 20:709–22
    [Google Scholar]
  139. 139.  Dang Y, Low WK, Xu J, Gehring NH, Dietz HC et al. 2009. Inhibition of nonsense-mediated mRNA decay by the natural product pateamine A through eukaryotic initiation factor 4AIII. J. Biol. Chem. 284:23613–21
    [Google Scholar]
  140. 140.  Dang Y, Kedersha N, Low WK, Romo D, Gorospe M et al. 2006. Eukaryotic initiation factor 2α-independent pathway of stress granule induction by the natural product pateamine A. J. Biol. Chem. 281:32870–78
    [Google Scholar]
  141. 141.  Bordeleau ME, Mori A, Oberer M, Lindqvist L, Chard LS et al. 2006. Functional characterization of IRESes by an inhibitor of the RNA helicase eIF4A. Nat. Chem. Biol. 2:213–20
    [Google Scholar]
  142. 142.  Tillotson J, Kedzior M, Guimarães L, Ross AB, Peters TL et al. 2017. ATP-competitive, marine derived natural products that target the DEAD box helicase, eIF4A. Bioorg. Med. Chem. Lett. 27:4082–85
    [Google Scholar]
  143. 143.  Iwasaki S, Floor SN, Ingolia NT 2016. Rocaglates convert DEAD-box protein eIF4A into a sequence-selective translational repressor. Nature 534:558–61
    [Google Scholar]
  144. 144.  Cencic R, Carrier M, Galicia-Vazquez G, Bordeleau ME, Sukarieh R et al. 2009. Antitumor activity and mechanism of action of the cyclopenta[b]benzofuran, silvestrol. PLOS ONE 4:e5223
    [Google Scholar]
  145. 145.  Lindqvist L, Robert F, Merrick W, Kakeya H, Fraser C et al. 2010. Inhibition of translation by cytotrienin A–a member of the ansamycin family. RNA 16:2404–13
    [Google Scholar]
  146. 146.  Kantarjian HM, Talpaz M, Santini V, Murgo A, Cheson B, O'Brien SM 2001. Homoharringtonine: history, current research, and future direction. Cancer 92:1591–605
    [Google Scholar]
  147. 147.  Gurel G, Blaha G, Moore PB, Steitz TA 2009. U2504 determines the species specificity of the A-site cleft antibiotics: the structures of tiamulin, homoharringtonine, and bruceantin bound to the ribosome. J. Mol. Biol. 389:146–56
    [Google Scholar]
  148. 148.  McClary B, Zinshteyn B, Meyer M, Jouanneau M, Pellegrino S et al. 2017. Inhibition of eukaryotic translation by the antitumor natural product agelastatin A. Cell Chem. Biol. 24:605–13.e5
    [Google Scholar]
  149. 149.  de Loubresse NG, Prokhorova I, Holtkamp W, Rodnina MV, Yusupova G, Yusupov M 2014. Structural basis for the inhibition of the eukaryotic ribosome. Nature 513:517–22
    [Google Scholar]
  150. 150.  Bhat M, Robichaud N, Hulea L, Sonenberg N, Pelletier J, Topisirovic I 2015. Targeting the translation machinery in cancer. Nat. Rev. Drug Discov. 14:261–78
    [Google Scholar]
  151. 151.  Schneider-Poetsch T, Ju J, Eyler DE, Dang Y, Bhat S et al. 2010. Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin. Nat. Chem. Biol. 6:209–17
    [Google Scholar]
  152. 152.  Dang Y, Schneider-Poetsch T, Eyler DE, Jewett JC, Bhat S et al. 2011. Inhibition of eukaryotic translation elongation by the antitumor natural product Mycalamide B. RNA 17:1578–88
    [Google Scholar]
  153. 153.  Lee S, Liu B, Huang SX, Shen B, Qian SB 2012. Global mapping of translation initiation sites in mammalian cells at single-nucleotide resolution. PNAS 109:E2424–32
    [Google Scholar]
  154. 154.  Han Y, Gao X, Liu B, Wan J, Zhang X, Qian SB 2014. Ribosome profiling reveals sequence-independent post-initiation pausing as a signature of translation. Cell Res 24:842–51
    [Google Scholar]
/content/journals/10.1146/annurev-biochem-060614-033923
Loading
/content/journals/10.1146/annurev-biochem-060614-033923
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error