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
Click here for help

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.

✖
Click here for structure editor
SMILES / InChI / InChIKey
Click here for help

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/)

✖
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/)
No information available.
Summary of Clinical Use Click here for help
Nusinersen was approved in December 2016 for the treatment of spinal muscular atrophy (SMA) in pediatric [4-5] and adult patients. Phase 1 trial results were reported in [2] and Phase 2 results in [3]. Nusinersen is administered directly to the central nervous system via intrathecal injection.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Nusinersen improves production of the SMN2 protein [7], whose loss causes the neuromuscular disease SMA. Nusinersen restores proper splicing of exon 7 which is abnormally spliced-out in SMA patients. Loss of exon 7 results in a truncated SMN2 protein (SMNdelta7 protein) which is unstable and inactive, leading to reduced levels of functional SMN protein. Nusinersen-induced restoration of SMN2 protein levels provides therapeutic benefit. The molecular mechanism underlying the ability of ASOs to modulate alternative splicing was originally described in [8].
External links Click here for help
For extended ADME data see the following:

Electronic Medicines Compendium (eMC)
Drugs.com
European Medicines Agency (EMA)