Discovery and Optimization of Small Molecule Splicing Modifiers of Survival Motor Neuron 2 as a Treatment for Spinal Muscular Atrophy

Journal of Medicinal Chemistry

Volumn 59, Issue 13, 2016, Pages 6070-6085

  Woll, Matthew G ^a   Qi, Hongyan ^a   Turpoff, Anthony ^a   Zhang, Nanjing ^a   Zhang, Xiaoyan ^a   Chen, Guangming ^a   Li, Chunshi ^a   Huang, Song ^a   Yang, Tianle ^a   Moon, Young Choon ^a   Lee, Chang Sun ^a   Choi, Soongyu ^a   Almstead, Neil G ^a   Naryshkin, Nikolai A ^a   Dakka, Amal ^a   Narasimhan, Jana ^a   Gabbeta, Vijayalakshmi ^a   Welch, Ellen ^a   Zhao, Xin ^a   Risher, Nicole ^a   Sheedy, Josephine ^a   Weetall, Marla ^a   Karp, Gary M ^a   more..

^a PTC THERAPEUTICS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 (4,6 DIMETHYLPYRAZOLO[1,5 A]PYRAZIN 2 YL) 7 (4 METHYLPIPERAZIN 1 YL) 4H PYRIDO[1,2 A]PYRIMIDIN 4 ONE; 2 (4,6 DIMETHYLPYRAZOLO[1,5 A]PYRAZIN 2 YL) 7 FLUORO 4H PYRIDO[ 1,2 A]PYRIMIDIN 4 ONE; 3 (2 BROMOACETYL) 7 FLUORO 1H ISOCHROMEN 1 ONE; 3 (2 BROMOACETYL) 7 FLUORO 2H CHROMEN 2 ONE; 3 (3,4 DIMETHOXYPHENYL) 7 (PIPERAZIN 1 YL) 2H CHROMEN 2 ONE; 3 (4 METHOXYPHENYL) 7 (PIPERAZIN 1 YL) 2H CHROMEN 2 ONE; 3 (6,8 DIMETHYLIMIDAZO[1,2 A]PYRAZIN 2 YL) 7 (3 METHYLPIPERAZIN 1 YL) 2H CHROMEN 2 ONE; 3 (6,8 DIMETHYLIMIDAZO[1,2 A]PYRAZIN 2 YL) 7 (4 METHYLPIPERAZIN 1 YL) 1H ISOCHROMEN 1 ONE; 3 (6,8 DIMETHYLIMIDAZO[1,2 A]PYRAZIN 2 YL) 7 FLUORO 1H ISOCHROMEN 1 ONE HYDROBROMIDE; 3 (6,8 DIMETHYLIMIDAZO[1,2 A]PYRAZIN 2 YL) 7 FLUORO 2H CHROMEN 2 ONE HYDROBROMIDE; 3 (BENZO[D]OXAZOL 2 YL) 7 (DIETHYLAMINO) 2H CHROMEN 2 ONE; 3 (BENZO[D]OXAZOL 2 YL) 7 (DIMETHYLAMINO) 2H CHROMEN 2 ONE; 3 (BENZO[D]OXAZOL 2 YL) 7 (PIPERAZIN 1 YL) 2H CHROMEN 2 ONE HYDROCHLORIDE; 3 (BENZO[D]OXAZOL 2 YL) 7 (PIPERIDIN 1 YL) 2H CHROMEN 2 ONE; 3 (BENZO[D]OXAZOL 2 YL) 7 MORPHOLINO 2H CHROMEN 2 ONE; 3 ACETYL 7 FLUORO 1H ISOCHROMEN 1 ONE; 3 ACETYL 7 FLUORO 2H CHROMEN 2 ONE; 3 PHENYL 7 (PIPERAZIN 1 YL) 2H CHROMEN 2 ONE; 7 FLUORO 3 (1 HYDROXYETHYL) 1H ISOCHROMEN 1 ONE; COUMARIN DERIVATIVE; ETHYL 2 (BENZO[D]OXAZOL 2 YL)ACETATE; ETHYL 3 (4,6 DIMETHYLPYRAZOLO[1,5 A]PYRAZIN 2 YL) 3 OXOPROPANOATE; ETHYL 4 CHLORO 6 METHYLPYRAZOLO[1,5 A]PYRAZINE 2 CARBOXYLATE; ETHYL 4 HYDROXY 6 METHYLPYRAZOLO[1,5 A]PYRAZINE 2 CARBOXYLATE; ETHYL 4,6 DIMETHYLPYRAZOLO[1,5 A]PYRAZINE 2 CARBOXYLATE; PROTEIN INHIBITOR; SMALL MOLECULE SPLICING MODIFIER OF SURVIVAL MOTOR NEURON 2 INHIBITOR; SURVIVAL MOTOR NEURON PROTEIN 2; TERT BUTYL 4 (4 FORMYL 3 HYDROXYPHENYL)PIPERAZINE 1 CARBOXYLATE; TERT BUTYL 4 [3 (BENZO[D]OXAZOL 2 YL) 2 OXO 2H CHROMEN 7 YL]PIPERAZINE 1 CARBOXYLATE; UNCLASSIFIED DRUG; MESSENGER RNA; MOLECULAR LIBRARY; SMN2 PROTEIN, HUMAN;

ALDOL REACTION; ALKYLATION; ALTERNATIVE RNA SPLICING; AMINATION; ANIMAL CELL; ANIMAL TISSUE; AREA UNDER THE CURVE; ARTICLE; BRAIN; BRAIN-TO-PLASMA RATIO; CLAISEN CONDENSATION; CONTROLLED STUDY; DRUG BLOOD LEVEL; DRUG PENETRATION; DRUG SYNTHESIS; EXON; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; IN VITRO STUDY; MEDIAN SURVIVAL TIME; MOUSE; NEWBORN; NONHUMAN; NUCLEOPHILICITY; PHARMACODYNAMICS; PHARMACOPHORE; PLASMA PROTEIN BINDING; POLYMERIZATION; QUADRICEPS FEMORIS MUSCLE; RAT; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; RING OPENING; RNA SPLICING; SONOGASHIRA REACTION; SPINAL CORD; SPINAL MUSCULAR ATROPHY; STRUCTURE ACTIVITY RELATION; SUZUKI REACTION; TRANSESTERIFICATION; ADMINISTRATION AND DOSAGE; ANIMAL; CELL LINE; CHEMISTRY; DRUG DEVELOPMENT; DRUG EFFECTS; GENETICS; HEK293 CELL LINE; KNOCKOUT MOUSE; MOLECULAR LIBRARY; MUSCULAR ATROPHY, SPINAL; PHARMACOLOGY; THERAPEUTIC USE;

ALTERNATIVE SPLICING; ANIMALS; CELL LINE; DRUG DISCOVERY; EXONS; HEK293 CELLS; HUMANS; MICE, KNOCKOUT; MUSCULAR ATROPHY, SPINAL; RNA, MESSENGER; SMALL MOLECULE LIBRARIES; STRUCTURE-ACTIVITY RELATIONSHIP; SURVIVAL OF MOTOR NEURON 2 PROTEIN;

EID: 84978634898     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.6b00460     Document Type: Article

References (27)

1. Lefebvre, S.; Bürglen, L.; Reboullet, S.; Clermont, O.; Burlet, P.; Viollet, L.; Benichou, B.; Cruaud, C.; Millasseau, P.; Zeviani, M.; Le Paslier, D.; Frézal, J.; Cohen, D.; Weissenbach, J.; Munnich, A.; Melki, J. Identification and characterization of a spinal muscular atrophy-determining gene Cell 1995, 80, 155-165 10.1016/0092-8674(95)90460-3
2. Lorson, C. L.; Hahnen, E.; Androphy, J.; Wirth, B. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy Proc. Natl. Acad. Sci. U. S. A. 1999, 96, 6307-6311 10.1073/pnas.96.11.6307
3. Cho, S.; Dreyfuss, G. A degron created by SMN2 exon 7 skipping is a principal contributor to spinal muscular atrophy severity Genes Dev. 2010, 24, 438-442 10.1101/gad.1884910
4. Burnett, B. G.; Muñoz, E.; Tandon, A.; Kwon, D. Y.; Sumner, C. J.; Fischbeck, K. H. Regulation of SMN protein stability Mol. Cell. Biol. 2009, 29, 1107-1115 10.1128/MCB.01262-08
5. Hua, Y.; Vickers, T. A.; Okunola, H. L.; Bennett, C. F.; Krainer, A. R. Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice Am. J. Hum. Genet. 2008, 82, 834-848 10.1016/j.ajhg.2008.01.014
6. Lim, S. R.; Hertel, K. J. Modulation of survival motor neuron pre-mRNA splicing by inhibition of alternative 3′ splice site pairing J. Biol. Chem. 2001, 276, 45476-45483 10.1074/jbc.M107632200
7. Porensky, P. N.; Mitrpant, C.; McGovern, V. L.; Bevan, A. K.; Foust, K. D.; Kaspar, B. K.; Wilton, S. D.; Burghes, A. H. M. A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse Hum. Mol. Genet. 2012, 21, 1625-1638 10.1093/hmg/ddr600
8. Passini, M. A.; Bu, J.; Richards, A. M.; Kinnecom, C.; Sardi, S. P.; Stanek, L. M.; Hua, Y.; Rigo, F.; Matson, J.; Hung, G.; Kaye, E. M.; Shihabuddin, L. S.; Krainer, A. R.; Bennett, C. F.; Cheng, S. H. Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy Sci. Transl. Med. 2011, 3, 72ra18 10.1126/scitranslmed.3001777
9. Hua, Y.; Sahashi, K.; Rigo, F.; Hung, G.; Horev, G.; Bennett, C. F.; Krainer, A. R. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model Nature 2011, 478, 123-126 10.1038/nature10485
10. Porensky, P. N.; Mitrpant, C.; McGovern, V. L.; Bevan, A. K.; Foust, K. D.; Kaspar, B. K.; Wilton, S. D.; Burghes, A. H. M. A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse Hum. Mol. Genet. 2012, 21, 1625-1638 10.1093/hmg/ddr600
11. Zhou, H.; Janghra, N.; Mitrpant, C.; Dickinson, R. L.; Anthony, K.; Price, L.; Eperon, I. C.; Wilton, S. D.; Morgan, J.; Muntoni, F. A novel morpholino oligomer targeting ISS-N1 improves rescue of severe spinal muscular atrophy transgenic mice Hum. Gene Ther. 2013, 24, 331-342 10.1089/hum.2012.211
12. Mitrpant, C.; Porensky, P.; Zhou, H.; Price, L.; Muntoni, F.; Fletcher, S.; Wilton, S. D.; Burghes, A. H. M. Improved antisense oligonucleotide design to suppress aberrant SMN2 gene transcript processing: Towards a treatment for spinal muscular atrophy PLoS One 2013, 8, e62114 10.1371/journal.pone.0062114
13. Osman, E. Y.; Miller, M. R.; Robbins, K. L.; Lombardi, A. M.; Atkinson, A. K.; Brehm, A. J.; Lorson, C. L. Morpholino antisense oligonucleotides targeting intronic repressor Element1 improve phenotype in SMA mouse models Hum. Mol. Genet. 2014, 23, 4832-4845 10.1093/hmg/ddu198
14. Grzeschik, S. M.; Ganta, M.; Prior, T. W.; Heavlin, W. D.; Wang, C. H. Hydroxyurea enhances SMN2 gene expression in spinal muscular atrophy cells Ann. Neurol. 2005, 58, 194-202 10.1002/ana.20548
15. Angelozzi, C.; Borgo, F.; Tiziano, F. D.; Martella, A.; Neri, G.; Brahe, C. Salbutamol increases SMN mRNA and protein levels in spinal muscular atrophy cells J. Med. Genet. 2008, 45, 29-31 10.1136/jmg.2007.051177
16. Hastings, M. L.; Berniac, J.; Liu, Y. H.; Abato, P.; Jodelka, F. M.; Barthel, L.; Kumar, S.; Dudley, C.; Nelson, M.; Larson, K.; Edmonds, J.; Bowser, T.; Draper, M.; Higgins, P.; Krainer, A. R. Tetracyclines that promote SMN2 exon 7 splicing as therapeutics for spinal muscular atrophy Sci. Transl. Med. 2009, 1, 5ra12 10.1126/scitranslmed.3000208
17. Chang, J.-G.; Hsieh-Li, H.-M.; Jong, Y.-J.; Wang, N. M.; Tsai, C.-H.; Li, H. Treatment of spinal muscular atrophy by sodium butyrate Proc. Natl. Acad. Sci. U. S. A. 2001, 98, 9808-9813 10.1073/pnas.171105098
18. Andreassi, C.; Angelozzi, C.; Tiziano, F. D.; Vitali, T.; De Vincenzi, E.; Boninsegna, A.; Villanova, M.; Bertini, E.; Pini, A.; Neri, G.; Brahe, C. Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy Eur. J. Hum. Genet. 2004, 12, 59-65 10.1038/sj.ejhg.5201102
19. Sumner, C. J.; Huynh, T. N.; Markowitz, J. A.; Perhac, J. S.; Hill, B.; Coovert, D. D.; Schussler, K.; Chen, X.; Jarecki, J.; Burghes, A. H. M.; Taylor, J. P.; Fischbeck, K. H. Valproic acid increases SMN levels in spinal muscular atrophy patient cells Ann. Neurol. 2003, 54, 647-654 10.1002/ana.10743
20. Avila, A. M.; Burnett, B. G.; Taye, A. A.; Gabanella, F.; Knight, M. A.; Hartenstein, P.; Cizman, Z.; Di Prospero, N. A.; Pellizzoni, L.; Fischbeck, K. H.; Sumner, C. J. Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy J. Clin. Invest. 2007, 117, 659-671 10.1172/JCI29562
21. Naryshkin, N. A.; Weetall, M.; Dakka, A.; Narasimhan, J.; Zhao, X.; Feng, Z.; Ling, K. K. Y.; Karp, G. M.; Qi, H.; Woll, M. G.; Chen, G.; Zhang, N.; Gabbeta, V.; Vazirani, P.; Bhattacharyya, A.; Furia, B.; Risher, N.; Sheedy, J.; Kong, R.; Ma, J.; Turpoff, A.; Lee, C. S.; Zhang, X.; Moon, Y.-C.; Trifillis, P.; Welch, E. M.; Colacino, J. M.; Babiak, J.; Almstead, N. G.; Peltz, S. W.; Eng, L. A.; Chen, K. S.; Mull, J. L.; Lynes, M. S.; Rubin, L. L.; Fontoura, P.; Santarelli, L.; Haehnke, D.; McCarthy, K. D.; Schmucki, R.; Ebeling, M.; Sivaramakrishnan, M.; Ko, C.-P.; Paushkin, S. V.; Ratni, H.; Gerlach, I.; Ghosh, A.; Metzger, F. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy Science 2014, 345, 688-693 10.1126/science.1250127
22. Palacino, J.; Swalley, S. E.; Song, C.; Cheung, A. K.; Shu, L.; Zhang, X.; Van Hoosear, M.; Shin, Y.; Chin, D. N.; Keller, C. G.; Beibel, M.; Renaud, N. A.; Smith, T. A.; Salcius, M.; Shi, X.; Hild, M.; Servais, R.; Jain, M.; Deng, L.; Bullock, C.; McLellan, M.; Schuierer, S.; Murphy, L.; Blommers, M. J. J.; Blaustein, C.; Berenshteyn, F.; Lacoste, A.; Thomas, J. R.; Roma, G.; Michaud, G. A.; Tseng, B. S.; Porter, J. A.; Myer, V. E.; Tallarico, J. A.; Hamann, L. G.; Curtis, D.; Fishman, M. C.; Dietrich, W. F.; Dales, N. A.; Sivasankaran, R. SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice Nat. Chem. Biol. 2015, 11, 511-517 10.1038/nchembio.1837
23. Lee, S.; Sivakumar, K.; Shin, W.-S.; Xie, F.; Wang, Q. Synthesis and anti-angiogenesis activity of coumarin derivatives Bioorg. Med. Chem. Lett. 2006, 16, 4596-4599 10.1016/j.bmcl.2006.06.007
24. Auberson, Y. Coumarines useful as biomarkers. WO 2003074519 A1, Sept 12, 2003.
25. Wu, Q.; Christensen, L. A.; Legerski, R. J.; Vasquez, K. M. Mismatch repair participates in error-free processing of DNA interstrand crosslinks in human cells EMBO Rep. 2005, 6, 551-556 10.1038/sj.embor.7400418
26. Le, T. T.; Pham, L. T.; Butchbach, M. E. R.; Zhang, H. L.; Monani, U. R.; Coovert, D. D.; Gavrilina, T. O.; Xing, L.; Bassell, G. J.; Burghes, A. H. M. SMNΔ7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN Hum. Mol. Genet. 2005, 14, 845-857 10.1093/hmg/ddi078
27. For additional data from survival studies, including body weight and righting reflex testing for compound 14, see: Zhao, X.; Feng, Z.; Ling, K. K. Y; Mollin, A.; Sheedy, J.; Yeh, S.; Petruska, J.; Narasimhan, J.; Dakka, A.; Welch, E. M.; Karp, G.; Chen, K. S.; Metzger, F.; Ratni, H.; Lotti, F.; Tisdale, S.; Naryshkin, N. A.; Pellizzoni, L.; Paushkin, S.; Ko, C.-P.; Weetall, M. Pharmacokinetics, pharmacodynamics, and efficacy of a small-molecule SMN2 splicing modifier in mouse models of spinal muscular atrophy. Hum. Mol. Genet. [Online early access]. DOI: 10.1093/hmg/ddw062. Published Online: Feb 29, 2016. http://hmg.oxfordjournals.org/content/early/2016/03/22/hmg.ddw062 (Accessed May 27, 2016).