nusinersen   Click here for help

GtoPdb Ligand ID: 9416

Synonyms: ASO-10-27 | BIIB-058 | BIIB058 | Ionis-SMNrx | ISIS 396443 | ISIS SMNRx | ISIS-SMNRx | ISIS396443 | Spinraza®
Approved drug
nusinersen is an approved drug (FDA (2016), EMA (2017))
Compound class: Nucleic acid
Comment: Nusinersen (ISIS 396443) is an antisense oligo(ribo)nucleotide (ASO) which induces survival motor neuron (SMN) protein expression from SMN2 genes with the exon 7-skipping mutation [7].
Nusinersen was initially available for use as a designated orphan drug (by the US FDA and EMA), and was the first drug to be fully approved for the treatment of spinal muscular atrophy (SMA).

The sequence contains 2'-O-(2-methoxyethyl) (2'-MOE)-oligoribonucleotides to reduce nuclease degradation and enhance binding affinity towards the complementary RNA. The full sequence is [2'-O-(2-methoxyethyl)](3'-5')(P-thio)(mU-mC-A-mC-mU-mU-mU-mC-A-mU-A-A-mU-G-mC-mU-G-G) as detailed in the INN record for the agent.
The sequence for nusinersen is claimed in patent WO2010148249A1 as SEQ ID NO: 1 [1].
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES COCCOC1C(OP(=O)(OCC2OC(C(C2OP(=O)(OCC2OC(C(C2OP(=O)(OCC2OC(C(C2OP(=O)(OCC2OC(C(C2OP(=O)(OCC2OC(C(C2OP(=O)(OCC2OC(C(C2OP(=O)(OCC2OC(C(C2OP(=O)(OCC2OC(C(C2OP(=O)(OCC2OC(C(C2O)OCCOC)n2cnc3c2nc(N)[nH]c3=O)S)OCCOC)n2cnc3c2nc(N)[nH]c3=O)S)OCCOC)n2cc(C)c(=O)[nH]c2=O)S)OCCOC)n2cc(C)c(nc2=O)N)S)OCCOC)n2cnc3c2nc(N)[nH]c3=O)S)OCCOC)n2cc(C)c(=O)[nH]c2=O)S)OCCOC)n2cnc3c2ncnc3N)S)OCCOC)n2cnc3c2ncnc3N)S)OCCOC)n2cc(C)c(=O)[nH]c2=O)S)C(OC1n1cnc2c1ncnc2N)COP(=O)(OC1C(COP(=O)(OC2C(COP(=O)(OC3C(COP(=O)(OC4C(COP(=O)(OC5C(COP(=O)(OC6C(COP(=O)(OC7C(COP(=O)(OC8C(CO)OC(C8OCCOC)n8cc(C)c(=O)[nH]c8=O)S)OC(C7OCCOC)n7cc(C)c(nc7=O)N)S)OC(C6OCCOC)n6cnc7c6ncnc7N)S)OC(C5OCCOC)n5cc(C)c(nc5=O)N)S)OC(C4OCCOC)n4cc(C)c(=O)[nH]c4=O)S)OC(C3OCCOC)n3cc(C)c(=O)[nH]c3=O)S)OC(C2OCCOC)n2cc(C)c(=O)[nH]c2=O)S)OC(C1OCCOC)n1cc(C)c(nc1=O)N)S
Isomeric SMILES COCCO[C@@H]1[C@H](OP(=O)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=O)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=O)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=O)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=O)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=O)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=O)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=O)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=O)(OC[C@H]2O[C@H]([C@@H]([C@@H]2O)OCCOC)n2cnc3c2nc(N)[nH]c3=O)S)OCCOC)n2cnc3c2nc(N)[nH]c3=O)S)OCCOC)n2cc(C)c(=O)[nH]c2=O)S)OCCOC)n2cc(C)c(nc2=O)N)S)OCCOC)n2cnc3c2nc(N)[nH]c3=O)S)OCCOC)n2cc(C)c(=O)[nH]c2=O)S)OCCOC)n2cnc3c2ncnc3N)S)OCCOC)n2cnc3c2ncnc3N)S)OCCOC)n2cc(C)c(=O)[nH]c2=O)S)[C@H](O[C@H]1n1cnc2c1ncnc2N)COP(=O)(O[C@@H]1[C@@H](COP(=O)(O[C@@H]2[C@@H](COP(=O)(O[C@@H]3[C@@H](COP(=O)(O[C@@H]4[C@@H](COP(=O)(O[C@@H]5[C@@H](COP(=O)(O[C@@H]6[C@@H](COP(=O)(O[C@@H]7[C@@H](COP(=O)(O[C@@H]8[C@@H](CO)O[C@H]([C@@H]8OCCOC)n8cc(C)c(=O)[nH]c8=O)S)O[C@H]([C@@H]7OCCOC)n7cc(C)c(nc7=O)N)S)O[C@H]([C@@H]6OCCOC)n6cnc7c6ncnc7N)S)O[C@H]([C@@H]5OCCOC)n5cc(C)c(nc5=O)N)S)O[C@H]([C@@H]4OCCOC)n4cc(C)c(=O)[nH]c4=O)S)O[C@H]([C@@H]3OCCOC)n3cc(C)c(=O)[nH]c3=O)S)O[C@H]([C@@H]2OCCOC)n2cc(C)c(=O)[nH]c2=O)S)O[C@H]([C@@H]1OCCOC)n1cc(C)c(nc1=O)N)S
InChI Key WWFDJIVIDXJAQR-FFWSQMGZSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
References
1. Bennett CF, Hung G, Rigo F, Krainer AR, Hua Y, Passini MA, Shihabuddin L, Cheng SH, Klinger KW. (2010)
Compositions and methods for modulation of smn2 splicing in a subject.
Patent number: WO2010148249A1. Assignee: Isis Pharmaceuticals, Inc., Genzyme Corporation, Cold Spring Harbor Laboratory. Priority date: 17/06/2009. Publication date: 23/12/2010.
2. Chiriboga CA, Swoboda KJ, Darras BT, Iannaccone ST, Montes J, De Vivo DC, Norris DA, Bennett CF, Bishop KM. (2016)
Results from a phase 1 study of nusinersen (ISIS-SMN(Rx)) in children with spinal muscular atrophy.
Neurology, 86 (10): 890-7. [PMID:26865511]
3. Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, Yamashita M, Rigo F, Hung G, Schneider E et al.. (2017)
Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study.
Lancet, 388 (10063): 3017-3026. [PMID:27939059]
4. Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, Chiriboga CA, Saito K, Servais L, Tizzano E et al.. (2017)
Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy.
N Engl J Med, 377 (18): 1723-1732. [PMID:29091570]
5. Mercuri E, Darras BT, Chiriboga CA, Day JW, Campbell C, Connolly AM, Iannaccone ST, Kirschner J, Kuntz NL, Saito K et al.. (2018)
Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy.
N Engl J Med, 378 (7): 625-635. [PMID:29443664]
6. Passini MA, Bu J, Richards AM, Kinnecom C, Sardi SP, Stanek LM, Hua Y, Rigo F, Matson J, Hung G et al.. (2011)
Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy.
Sci Transl Med, 3 (72): 72ra18. [PMID:21368223]
7. Rigo F, Chun SJ, Norris DA, Hung G, Lee S, Matson J, Fey RA, Gaus H, Hua Y, Grundy JS et al.. (2014)
Pharmacology of a central nervous system delivered 2'-O-methoxyethyl-modified survival of motor neuron splicing oligonucleotide in mice and nonhuman primates.
J Pharmacol Exp Ther, 350 (1): 46-55. [PMID:24784568]
8. Rigo F, Hua Y, Chun SJ, Prakash TP, Krainer AR, Bennett CF. (2012)
Synthetic oligonucleotides recruit ILF2/3 to RNA transcripts to modulate splicing.
Nat Chem Biol, 8 (6): 555-61. [PMID:22504300]