The spliceosome as a target of novel antitumour drugs

Nature Reviews Drug Discovery

Volumn 11, Issue 11, 2012, Pages 847-859

  Bonnal, Sophie ^a,b   Vigevani, Luisa ^a,b   Valcárcel, Juan ^a,b,c  

^a CENTRE FOR GENOMIC REGULATION CRG   (Spain)

^b UNIVERSITAT POMPEU FABRA   (Spain)

^c INSTITUCIÓ CATALANA DE RECERCA I ESTUDIS AVANÇATS ICREA   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

6 FORMYLAMINO 12,13 DIHYDRO 1,11 DIHYDROXY 5H INDOLO[2,3 A]PYRROLO[3,4 C]CARBAZOLE 5,7(6H) DIONE 13 GLUCOSIDE; AMILORIDE; ANTINEOPLASTIC AGENT; E 7107; FR 901463; FR 901464; FR 901465; GEX 1A; GEX 1Q1; GEX 1Q2; GEX 1Q3; GEX 1Q4; GEX 1Q5; INDOLE DERIVATIVE; ISOGINKGETIN; MEAYAMYCIN; MEAYAMYCIN B; PLADIENOLIDE A; PLADIENOLIDE B; PLADIENOLIDE C; PLADIENOLIDE D; PLADIENOLIDE E; PLADIENOLIDE F; PLADIENOLIDE G; SPLICEOSTATIN A; STEROID; SUDEMYCIN C1; SUDEMYCIN E; SUDEMYCIN F; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ALTERNATIVE RNA SPLICING; ANTINEOPLASTIC ACTIVITY; CANCER CHEMOTHERAPY; CANCER GROWTH; CARCINOGENESIS; CHRONIC LYMPHATIC LEUKEMIA; DRUG BINDING SITE; DRUG STRUCTURE; DRUG TARGETING; GENE EXPRESSION REGULATION; GENE FUNCTION; GENE MUTATION; HEART FAILURE; HUMAN; INTRON; MOLECULAR RECOGNITION; MYELODYSPLASTIC SYNDROME; NONHUMAN; PRIORITY JOURNAL; PROTEIN NUCLEIC ACID INTERACTION; REVIEW; RNA TRANSPORT; SPLICEOSOME;

ANIMALS; ANTINEOPLASTIC AGENTS; BACTERIA; DISEASE PROGRESSION; DRUG DESIGN; FERMENTATION; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; MOLECULAR TARGETED THERAPY; NEOPLASMS; PHOSPHOPROTEINS; RIBONUCLEOPROTEIN, U2 SMALL NUCLEAR; SPLICEOSOMES;

EID: 84868355027     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd3823     Document Type: Review

References (122)

1. Moore, M. J. & Proudfoot, N. J. Pre-mRNA processing reaches back to transcription and ahead to translation. Cell 136, 688-700 (2009).
2. Wahl, M. C., Will, C. L. & Luhrmann, R. The spliceosome: design principles of a dynamic RNP machine. Cell 136, 701-718 (2009).
3. Will, C. L. & Luhrmann, R. Spliceosome structure and function. Cold Spring. Harb. Perspect. Biol. 3, a003707 (2011).
4. Blencowe, B. J. Alternative splicing: new insights from global analyses. Cell 126, 37-47 (2006). (Pubitemid 44040990)
5. Nilsen, T. W. & Graveley, B. R. Expansion of the eukaryotic proteome by alternative splicing. Nature 463, 457-463 (2010).
6. Cooper, T. A., Wan, L. & Dreyfuss, G. RNA and disease. Cell 136, 777-793 (2009).
7. Kalsotra, A. & Cooper, T. A. Functional consequences of developmentally regulated alternative splicing. Nature Rev. Genet. 12, 715-729 (2011).
8. David, C. J. & Manley, J. L. Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged. Genes Dev. 24, 2343-2364 (2010).
9. Kaida, D., Schneider-Poetsch, T. & Yoshida, M. Splicing in oncogenesis and tumor suppression. Cancer Sci. 103, 1611-1616 (2012).
10. Pio, R. & Montuenga, L. M. Alternative splicing in lung cancer. J. Thorac. Oncol. 4, 674-678 (2009).
11. Harper, S. J. & Bates, D. O. VEGF-A splicing: the key to anti-angiogenic therapeutics? Nature Rev. Cancer 8, 880-887 (2008).
12. Cheng, J. et al. Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science 263, 1759-1762 (1994). (Pubitemid 24131584)
13. Christofk, H. R. et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452, 230-233 (2008). (Pubitemid 351380249)
14. Jeyaraj, S., O'Brien, D. M. & Chandler, D. S. MDM2 and MDM4 splicing: an integral part of the cancer spliceome. Front. Biosci. 14, 2647-2656 (2009).
15. Kole, R., Krainer, A. R. & Altman, S. RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nature Rev. Drug Discov. 11, 125-140 (2012).
16. Hua, Y. et al. Antisense correction of SMN2 splicing in the CNS rescues necrosis in a type III SMA mouse model. Genes Dev. 24, 1634-1644 (2010).
17. Hua, Y. et al. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 478, 123-126 (2011).
18. Nakajima, H. et al. New antitumor substances, FR901463, FR901464 and FR901465. II. Activities against experimental tumors in mice and mechanism of action. J. Antibiot. (Tokyo) 49, 1204-1211 (1996).
19. Nakajima, H. et al. New antitumor substances, FR901463, FR901464 and FR901465. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities. J. Antibiot. (Tokyo) 49, 1196-1203 (1996).
20. Nakajima, H., Takase, S., Terano, H. & Tanaka, H. New antitumor substances, FR901463, FR901464 and FR901465. III. Structures of FR901463, FR901464 and FR901465. J. Antibiot. (Tokyo) 50, 96-99 (1997). (Pubitemid 27078067)
21. Mizui, Y. et al. Pladienolides, new substances from culture of Streptomyces platensis Mer-11107. III. In vitro and in vivo antitumor activities. J. Antibiot. (Tokyo) 57, 188-196 (2004). (Pubitemid 38489677)
22. Sakai, T., Asai, N., Okuda, A., Kawamura, N. & Mizui, Y. Pladienolides, new substances from culture of Streptomyces platensis Mer-11107. II. Physico-chemical properties and structure elucidation. J. Antibiot. (Tokyo) 57, 180-187 (2004). (Pubitemid 38489676)
23. Sakai, T. et al. Pladienolides, new substances from culture of Streptomyces platensis Mer-11107. I. Taxonomy, fermentation, isolation and screening. J. Antibiot. (Tokyo) 57, 173-179 (2004). (Pubitemid 38489675)
24. Sakai, Y. et al. GEX1 compounds, novel antitumor antibiotics related to herboxidiene, produced by Streptomyces sp. II. The effects on cell cycle progression and gene expression. J. Antibiot. (Tokyo) 55, 863-872 (2002). (Pubitemid 35315001)
25. Sakai, Y. et al. GEX1 compounds, novel antitumor antibiotics related to herboxidiene, produced by Streptomyces sp. I. Taxonomy, production, isolation, physicochemical properties and biological activities. J. Antibiot. (Tokyo) 55, 855-862 (2002). (Pubitemid 35315000)
26. Albert, B. J. et al. Meayamycin inhibits pre-messenger RNA splicing and exhibits picomolar activity against multidrug-resistant cells. Mol. Cancer Ther. 8, 2308-2318 (2009).
27. Kaida, D. et al. Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA. Nature Chem. Biol. 3, 576-583 (2007). (Pubitemid 47294395)
28. Kotake, Y. et al. Splicing factor SF3b as a target of the antitumor natural product pladienolide. Nature Chem. Biol. 3, 570-575 (2007). (Pubitemid 47294394)
29. Fan, L., Lagisetti, C., Edwards, C. C., Webb, T. R. & Potter, P. M. Sudemycins, novel small molecule analogues of FR901464, induce alternative gene splicing. ACS Chem. Biol. 6, 582-589 (2011).
30. Lagisetti, C. et al. Synthetic mRNA splicing modulator compounds with in vivo antitumor activity. J. Med. Chem. 52, 6979-6990 (2009).
31. Lagisetti, C. et al. Antitumor compounds based on a natural product consensus pharmacophore. J. Med. Chem. 51, 6220-6224 (2008).
32. Webb, T. R., Joyner, A. S. & Potter, P. M. The development and application of small molecule modulators of SF3b as therapeutic agents for cancer. Drug Discov. Today 3 Aug 2012 (doi:10.1016/j. drudis.2012.07.013).
33. Hasegawa, M. et al. Identification of SAP155 as the target of GEX1A (Herboxidiene), an antitumor natural product. ACS Chem. Biol. 6, 229-233 (2011).
34. Yokoi, A. et al. Biological validation that SF3b is a target of the antitumor macrolide pladienolide. FEBS J. 278, 4870-4880 (2011).
35. Corrionero, A., Minana, B. & Valcarcel, J. Reduced fidelity of branch point recognition and alternative splicing induced by the anti-tumor drug spliceostatin A. Genes Dev. 25, 445-459 (2011).
36. Roybal, G. A. & Jurica, M. S. Spliceostatin A inhibits spliceosome assembly subsequent to prespliceosome formation. Nucleic Acids Res. 38, 6664-6672 (2010).
37. Schmidt, U. et al. Real-time imaging of cotranscriptional splicing reveals a kinetic model that reduces noise: implications for alternative splicing regulation. J. Cell Biol. 193, 819-829 (2011).
38. Abu Dayyeh, B. K., Quan, T. K., Castro, M. & Ruby, S. W. Probing interactions between the U2 small nuclear ribonucleoprotein and the DEAD-box protein, Prp5. J. Biol. Chem. 277, 20221-20233 (2002). (Pubitemid 34967314)
39. Perriman, R. & Ares, M. Jr. Invariant U2 snRNA nucleotides form a stem loop to recognize the intron early in splicing. Mol. Cell 38, 416-427 (2010).
40. Folco, E. G., Coil, K. E. & Reed, R. 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, 440-444 (2011).
41. An, M. & Henion, P. D. The zebrafish sf3b1b460 mutant reveals differential requirements for the sf3b1 pre-mRNA processing gene during neural crest development. Int. J. Dev. Biol. 56, 223-237 (2012).
42. Martins, S. B. et al. Spliceosome assembly is coupled to RNA polymerase II dynamics at the 3(f) end of human genes. Nature Struct. Mol. Biol. 18, 1115-1123 (2011).
43. Brody, Y. et al. The in vivo kinetics of RNA polymerase II elongation during co-transcriptional splicing. PLoS Biol. 9, e1000573 (2011).
44. Furumai, R. et al. Spliceostatin A blocks angiogenesis by inhibiting global gene expression including VEGF. Cancer Sci. 101, 2483-2489 (2010).
45. Allende-Vega, N. et al. p53 is activated in response to disruption of the pre-mRNA splicing machinery. Oncogene 20 Feb 2012 (doi:10.1038/onc.2012.38).
46. Hahn, C. N. & Scott, H. S. Spliceosome mutations in hematopoietic malignancies. Nature Genet. 44, 9-10 (2012).
47. Edery, P. et al. Association of TALS developmental disorder with defect in minor splicing component U4atac snRNA. Science 332, 240-243 (2011).
48. He, H. et al. Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I. Science 332, 238-240 (2011).
49. Golas, M. M., Sander, B., Will, C. L., Luhrmann, R. & Stark, H. Major conformational change in the complex SF3b upon integration into the spliceosomal U11/U12 di-snRNP as revealed by electron cryomicroscopy. Mol. Cell 17, 869-883 (2005). (Pubitemid 40386947)
50. Massiello, A., Roesser, J. R. & Chalfant, C. E. SAP155 binds to ceramide-responsive RNA cis-element 1 and regulates the alternative 5? splice site selection of Bcl-x pre-mRNA. FASEB J. 20, 1680-1682 (2006).
51. Friend, K., Lovejoy, A. F. & Steitz, J. A. U2 snRNP binds intronless histone pre-mRNAs to facilitate U7-snRNP-dependent 3(f) end formation. Mol. Cell 28, 240-252 (2007). (Pubitemid 47600001)
52. Kyburz, A., Friedlein, A., Langen, H. & Keller, W. Direct interactions between subunits of CPSF and the U2 snRNP contribute to the coupling of pre-mRNA 3(f) end processing and splicing. Mol. Cell 23, 195-205 (2006). (Pubitemid 44062372)
53. Di Giammartino, D. C., Nishida, K. & Manley, J. L. Mechanisms and consequences of alternative polyadenylation. Mol. Cell 43, 853-866 (2011).
54. Neilson, J. R. & Sandberg, R. Heterogeneity in mammalian RNA 3(f) end formation. Exp. Cell Res. 316, 1357-1364 (2010).
55. Isono, K., Mizutani-Koseki, Y., Komori, T., Schmidt-Zachmann, M. S. & Koseki, H. Mammalian polycomb-mediated repression of Hox genes requires the essential spliceosomal protein Sf3b1. Genes Dev. 19, 536-541 (2005). (Pubitemid 40314986)
56. Abdel-Wahab, O. & Levine, R. The spliceosome as an indicted conspirator in myeloid malignancies. Cancer Cell 20, 420-423 (2011).
57. Damm, F. et al. Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes. Blood 119, 3211-3218 (2012).
58. Visconte, V., Makishima, H., Maciejewski, J. P. & Tiu, R. V. Emerging roles of the spliceosomal machinery in myelodysplastic syndromes and other hematological disorders. Leukemia 15 May 2012 (doi:10.1038/leu.2012.130).
59. Lindsley, R. C. & Ebert, B. L. Molecular pathophysiology of myelodysplastic syndromes. Annu. Rev. Pathol. 28 Aug 2012 (doi:10.1146/annurev- pathol-011811-132436).
60. Murati, A. et al. Myeloid malignancies: mutations, models and management. BMC Cancer 12, 304 (2012).
61. Damm, F., Nguyen-Khac, F., Fontenay, M. & Bernard, O. A. Spliceosome and other novel mutations in chronic lymphocytic leukemia and myeloid malignancies. Leukemia 26, 2027-2031 (2012).
62. Makishima, H. et al. Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. Blood 119, 3203-3210 (2012).
63. Yoshida, K. et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 478, 64-69 (2011).
64. Papaemmanuil, E. et al. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N. Engl. J. Med. 365, 1384-1395 (2011).
65. Hirabayashi, S. et al. Spliceosomal gene aberrations are rare, coexist with oncogenic mutations, and are unlikely to exert a driver effect in childhood MDS and JMML. Blood 119, e96-e99 (2012).
66. Matsuda, K. et al. Long-term haematological improvement after non-intensive or no chemotherapy in juvenile myelomonocytic leukaemia and poor correlation with adult myelodysplasia spliceosome-related mutations. Br. J. Haematol. 157, 647-650 (2012).
67. Lasho, T. L. et al. SF3B1 mutations in primary myelofibrosis: clinical, histopathology and genetic correlates among 155 patients. Leukemia 26, 1135-1137 (2012).
68. Visconte, V. et al. SF3B1, a splicing factor is frequently mutated in refractory anemia with ring sideroblasts. Leukemia 26, 542-545 (2012).
69. Malcovati, L. et al. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood 118, 6239-6246 (2011).
70. Cui, R. et al. Clinical importance of SF3B1 mutations in Chinese with myelodysplastic syndromes with ring sideroblasts. Leuk. Res. 36, 1428-1433 (2012).
71. Patnaik, M. M. et al. SF3B1 mutations are prevalent in myelodysplastic syndromes with ring sideroblasts but do not hold independent prognostic value. Blood 119, 569-572 (2012).
72. Jeromin, S. et al. High frequencies of SF3B1 and JAK2 mutations in refractory anemia with ring sideroblasts associated with marked thrombocytosis strengthen the assignment to the category of myelodysplastic/myeloproliferative neoplasms. Haematologica 28 Aug 2012 (doi:10.3324/haematol.2012.072538).
73. Visconte, V. et al. SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes. Blood 23 Jul 2012 (doi:10.1182/blood-2012-05-430876).
74. Thol, F. et al. Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes. Blood 119, 3578-3584 (2012).
75. Quesada, V. et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nature Genet. 44, 47-52 (2012).
76. Wang, L. et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N. Engl. J. Med. 365, 2497-2506 (2011).
77. Rossi, D. et al. Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine- refractoriness. Blood 118, 6904-6908 (2011).
78. Quesada, V., Ramsay, A. J. & Lopez-Otin, C. Chronic lymphocytic leukemia with SF3B1 mutation. N. Engl. J. Med. 366, 2530 (2012).
79. Pleasance, E. D. et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463, 191-196 (2010).
80. Wood, L. D. et al. The genomic landscapes of human breast and colorectal cancers. Science 318, 1108-1113 (2007). (Pubitemid 350134889)
81. Ellis, M. J. et al. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature 486, 353-360 (2012).
82. Groves, M. R. & Barford, D. Topological characteristics of helical repeat proteins. Curr. Opin. Struct. Biol. 9, 383-389 (1999). (Pubitemid 29454508)
83. Xing, Y. et al. Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins. Cell 127, 341-353 (2006). (Pubitemid 44572378)
84. Golas, M. M., Sander, B., Will, C. L., Luhrmann, R. & Stark, H. Molecular architecture of the multiprotein splicing factor SF3b. Science 300, 980-984 (2003). (Pubitemid 36548885)
85. Graubert, T. A. et al. Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nature Genet. 44, 53-57 (2012).
86. Wu, S. J. et al. The clinical implication of SRSF2 mutation in patients with myelodysplastic syndrome and its stability during disease evolution. Blood 29 Aug 2012 (doi:10.1182/blood-2012-02-412296).
87. Ogle, J. M. & Ramakrishnan, V. Structural insights into translational fidelity. Annu. Rev. Biochem. 74, 129-177 (2005). (Pubitemid 40995504)
88. Berg, M. G. et al. A quantitative high throughput in vitro splicing assay identifies inhibitors of spliceosome catalysis. Mol. Cell. Biol. 32, 1271-1283 (2012).
89. O'Brien, K., Matlin, A. J., Lowell, A. M. & Moore, M. J. The biflavonoid isoginkgetin is a general inhibitor of pre-mRNA splicing. J. Biol. Chem. 283, 33147-33154 (2008).
90. Shkreta, L. et al. Anticancer drugs affect the alternative splicing of Bcl-x and other human apoptotic genes. Mol. Cancer Ther. 7, 1398-1409 (2008).
91. Roca, X. et al. Widespread recognition of 5(r) splice sites by noncanonical base-pairing to U1 snRNA involving bulged nucleotides. Genes Dev. 26, 1098-1109 (2012).
92. Smith, D. J., Konarska, M. M. & Query, C. C. Insights into branch nucleophile positioning and activation from an orthogonal pre-mRNA splicing system in yeast. Mol. Cell 34, 333-343 (2009).
93. Gozani, O., Potashkin, J. & Reed, R. A potential role for U2AF-SAP 155 interactions in recruiting U2 snRNP to the branch site. Mol. Cell. Biol. 18, 4752-4760 (1998). (Pubitemid 28343060)
94. Warkocki, Z. et al. Reconstitution of both steps of Saccharomyces cerevisiae splicing with purified spliceosomal components. Nature Struct. Mol. Biol. 16, 1237-1243 (2009).
95. Lardelli, R. M., Thompson, J. X., Yates, J. R. & Stevens, S. W. Release of SF3 from the intron branchpoint activates the first step of pre-mRNA splicing. RNA 16, 516-528 (2010).
96. Wang, C. et al. Phosphorylation of spliceosomal protein SAP 155 coupled with splicing catalysis. Genes Dev. 12, 1409-1414 (1998). (Pubitemid 28243626)
97. Egecioglu, D. E. & Chanfreau, G. Proofreading and spellchecking: a two-tier strategy for pre-mRNA splicing quality control. RNA 17, 383-389 (2011).
98. Wang, Z. & Burge, C. B. Splicing regulation: from a parts list of regulatory elements to an integrated splicing code. RNA 14, 802-813 (2008). (Pubitemid 351574901)
99. Chen, M. & Manley, J. L. Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nature Rev. Mol. Cell Biol. 10, 741-754 (2009).
100. Witten, J. T. & Ule, J. Understanding splicing regulation through RNA splicing maps. Trends Genet. 27, 89-97 (2011).
101. Barash, Y. et al. Deciphering the splicing code. Nature 465, 53-59 (2010).
102. Heyd, F. & Lynch, K. W. Degrade, move, regroup: signaling control of splicing proteins. Trends Biochem. Sci. 36, 397-404 (2011).
103. Kornblihtt, A. R. Coupling transcription and alternative splicing. Adv. Exp. Med. Biol. 623, 175-189 (2007).
104. Luco, R. F., Allo, M., Schor, I. E., Kornblihtt, A. R. & Misteli, T. Epigenetics in alternative pre-mRNA splicing. Cell 144, 16-26 (2011).
105. Zaharieva, E., Chipman, K. & Soller, M. Alternative splicing interference by xenobiotics. Toxicology 296, 1-12 (2012).
106. Yoon, S. O., Shin, S., Lee, H. J., Chun, H. K. & Chung, A. S. Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt-dependent matrix metalloproteinase-9 expression. Mol. Cancer Ther. 5, 2666-2675 (2006). (Pubitemid 44848993)
107. Stoilov, P., Lin, C. H., Damoiseaux, R., Nikolic, J. & Black, D. L. A high-throughput screening strategy identifies cardiotonic steroids as alternative splicing modulators. Proc. Natl Acad. Sci. USA 105, 11218-11223 (2008).
108. Anderson, E. S. et al. The cardiotonic steroid digitoxin regulates alternative splicing through depletion of the splicing factors SRSF3 and TRA2B. RNA 18, 1041-1049 (2012).
109. Soret, J. et al. Selective modification of alternative splicing by indole derivatives that target serine-arginine-rich protein splicing factors. Proc. Natl Acad. Sci. USA 102, 8764-8769 (2005). (Pubitemid 40862809)
110. Ghigna, C. et al. Pro-metastatic splicing of Ron proto-oncogene mRNA can be reversed: therapeutic potential of bifunctional oligonucleotides and indole derivatives. RNA Biol. 7, 495-503 (2010).
111. Mermoud, J. E., Cohen, P. & Lamond, A. I. Ser/Thr-specific protein phosphatases are required for both catalytic steps of pre-mRNA splicing. Nucleic Acids Res. 20, 5263-5269 (1992).
112. Zhang, M. L., Lorson, C. L., Androphy, E. J. & Zhou, J. An in vivo reporter system for measuring increased inclusion of exon 7 in SMN2 mRNA: potential therapy of SMA. Gene Ther. 8, 1532-1538 (2001). (Pubitemid 33061891)
113. Zhang, Z. et al. Synthesis and characterization of pseudocantharidins, novel phosphatase modulators that promote the inclusion of exon 7 into the SMN (survival of motoneuron) pre-mRNA. J. Biol. Chem. 286, 10126-10136 (2011).
114. Pilch, B. et al. Specific inhibition of serine-and arginine-rich splicing factors phosphorylation, spliceosome assembly, and splicing by the antitumor drug NB-506. Cancer Res. 61, 6876-6884 (2001). (Pubitemid 32896513)
115. Muraki, M. et al. Manipulation of alternative splicing by a newly developed inhibitor of Clks. J. Biol. Chem. 279, 24246-24254 (2004). (Pubitemid 38725286)
116. Nishida, A. et al. Chemical treatment enhances skipping of a mutated exon in the dystrophin gene. Nature Commun. 2, 308 (2011).
117. Fukuhara, T. et al. Utilization of host SR protein kinases and RNA-splicing machinery during viral replication. Proc. Natl Acad. Sci. USA 103, 11329-11333 (2006). (Pubitemid 44156517)
118. Chang, J. G. et al. Small molecule amiloride modulates oncogenic RNA alternative splicing to devitalize human cancer cells. PLoS ONE 6, e18643 (2011).
119. Chang, W. H. et al. Amiloride modulates alternative splicing in leukemic cells and resensitizes Bcr-AblT315I mutant cells to imatinib. Cancer Res. 71, 383-392 (2011).
120. Younis, I. et al. Rapid-response splicing reporter screens identify differential regulators of constitutive and alternative splicing. Mol. Cell. Biol. 30, 1718-1728 (2010).
121. Ghosh, A. K. & Anderson, D. D. Enantioselective total synthesis of pladienolide B: a potent spliceosome inhibitor. Org. Lett. 14, 4730-4733 (2012).
122. Osman, S. et al. Structural requirements for the antiproliferative activity of pre-mRNA splicing inhibitor FR901464. Chemistry 17, 895-904 (2011).