Discovery of Small Molecule Splicing Modulators of Survival Motor Neuron‑2 (SMN2) for the Treatment of Spinal Muscular Atrophy (SMA)

Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists; however it codes...

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Published inJournal of medicinal chemistry Vol. 61; no. 24; pp. 11021 - 11036
Main Authors Cheung, Atwood K, Hurley, Brian, Kerrigan, Ryan, Shu, Lei, Chin, Donovan N, Shen, Yiping, O’Brien, Gary, Sung, Moo Je, Hou, Ying, Axford, Jake, Cody, Emma, Sun, Robert, Fazal, Aleem, Tomlinson, Ronald C, Jain, Monish, Deng, Lin, Hoffmaster, Keith, Song, Cheng, Van Hoosear, Mailin, Shin, Youngah, Servais, Rebecca, Towler, Christopher, Hild, Marc, Curtis, Daniel, Dietrich, William F, Hamann, Lawrence G, Briner, Karin, Chen, Karen S, Kobayashi, Dione, Sivasankaran, Rajeev, Dales, Natalie A
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 27.12.2018
Amer Chemical Soc
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Abstract Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists; however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070/branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA. Branaplam (1) originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multiparameter lead optimization. In a severe mouse SMA model, branaplam treatment increased full-length SMN RNA and protein levels, and extended survival. Currently, branaplam is in clinical studies for SMA.
AbstractList Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a loss of function mutation of the survival motor neuron 1 (SMN1) gene. In humans, a second closely related gene SMN2 exists; however it codes for a less stable SMN protein. In recent years, significant progress has been made toward disease modifying treatments for SMA by modulating SMN2 pre-mRNA splicing. Herein, we describe the discovery of LMI070/branaplam, a small molecule that stabilizes the interaction between the spliceosome and SMN2 pre-mRNA. Branaplam (1) originated from a high-throughput phenotypic screening hit, pyridazine 2, and evolved via multiparameter lead optimization. In a severe mouse SMA model, branaplam treatment increased full-length SMN RNA and protein levels, and extended survival. Currently, branaplam is in clinical studies for SMA.
Author O’Brien, Gary
Kerrigan, Ryan
Kobayashi, Dione
Towler, Christopher
Shen, Yiping
Dietrich, William F
Shin, Youngah
Sun, Robert
Deng, Lin
Cheung, Atwood K
Cody, Emma
Van Hoosear, Mailin
Hild, Marc
Hou, Ying
Axford, Jake
Hamann, Lawrence G
Fazal, Aleem
Chen, Karen S
Hurley, Brian
Curtis, Daniel
Tomlinson, Ronald C
Briner, Karin
Chin, Donovan N
Dales, Natalie A
Shu, Lei
Hoffmaster, Keith
Servais, Rebecca
Sung, Moo Je
Jain, Monish
Song, Cheng
Sivasankaran, Rajeev
AuthorAffiliation SMA Foundation
Novartis Pharmaceuticals
Novartis Institutes for BioMedical Research
AuthorAffiliation_xml – name: SMA Foundation
– name: Novartis Institutes for BioMedical Research
– name: Novartis Pharmaceuticals
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  orcidid: 0000-0002-2210-6362
  surname: Cheung
  fullname: Cheung, Atwood K
  email: atwood.cheung@novartis.com
  organization: Novartis Institutes for BioMedical Research
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  givenname: Brian
  surname: Hurley
  fullname: Hurley, Brian
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  surname: Tomlinson
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  organization: Novartis Institutes for BioMedical Research
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  organization: Novartis Pharmaceuticals
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  givenname: Marc
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  fullname: Hild, Marc
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  organization: Novartis Institutes for BioMedical Research
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  givenname: William F
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  givenname: Lawrence G
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  givenname: Dione
  surname: Kobayashi
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  organization: SMA Foundation
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  fullname: Sivasankaran, Rajeev
  organization: Novartis Institutes for BioMedical Research
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  givenname: Natalie A
  surname: Dales
  fullname: Dales, Natalie A
  email: natalie.dales@novartis.com
  organization: Novartis Institutes for BioMedical Research
BackLink https://www.ncbi.nlm.nih.gov/pubmed/30407821$$D View this record in MEDLINE/PubMed
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Snippet Spinal muscular atrophy (SMA), a rare neuromuscular disorder, is the leading genetic cause of death in infants and toddlers. SMA is caused by the deletion or a...
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SubjectTerms Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
Title Discovery of Small Molecule Splicing Modulators of Survival Motor Neuron‑2 (SMN2) for the Treatment of Spinal Muscular Atrophy (SMA)
URI http://dx.doi.org/10.1021/acs.jmedchem.8b01291
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