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

Journal of Medicinal Chemistry
Atwood K CheungNatalie A Dales

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.

References

Nov 7, 1998·Nature Genetics·D K GavrilovC H Wang
May 26, 1999·Proceedings of the National Academy of Sciences of the United States of America·C L LorsonB Wirth
Dec 10, 1999·Journal of Medicinal Chemistry· AjayM A Murcko
May 31, 2003·Nature Reviews. Drug Discovery·Bernard Fermini, Anthony A Fossa
Aug 18, 2006·Journal of Medicinal Chemistry·Craig JamiesonGrant Wishart
Jan 26, 2007·Bioorganic & Medicinal Chemistry Letters·I Wayne CheneyJim Z Wu
Sep 1, 2007·Journal of Child Neurology·Charlotte J Sumner
Feb 1, 2008·Journal of Medicinal Chemistry·M Paul Gleeson
Jun 24, 2008·Lancet·Mitchell R Lunn, Ching H Wang
Aug 12, 2009·Neurobiology of Disease·Phil Jeffrey, Scott Summerfield
Sep 18, 2009·Nature·Shih-Min A HuangFeng Cong
Dec 17, 2009·Bioorganic & Medicinal Chemistry Letters·Robert J GleaveMartin E Swarbrick
Mar 4, 2011·Science Translational Medicine·Marco A PassiniSeng H Cheng
Apr 13, 2011·Archives of Neurology·Stephen J Kolb, John T Kissel
Apr 20, 2011·Proceedings of the National Academy of Sciences of the United States of America·Aurelio BonaviaSimon M Bushell
Aug 4, 2011·European Journal of Human Genetics : EJHG·Elaine A SugarmanBernice A Allitto
Mar 3, 2012·Molecules and Cells·Jianhua ZhouHaihong Shen
Mar 13, 2013·Antimicrobial Agents and Chemotherapy·Daryl L RichieDominic Hoepfner
Mar 19, 2014·Nature Chemical Biology·Frederic BassilanaSarah J Luchansky
Dec 17, 2014·Journal of Medicinal Chemistry·Zoran Rankovic
Jun 2, 2015·Nature Chemical Biology·James PalacinoRajeev Sivasankaran
Nov 2, 2017·The New England Journal of Medicine·Jerry R MendellBrian K Kaspar

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Citations

Jul 3, 2019·Scientific Reports·Erkan Y OsmanChristian L Lorson
Nov 2, 2019·Future Medicinal Chemistry·Ravindra N Singh
May 19, 2020·SLAS Discovery·Hafeez S HaniffHelen L Lightfoot
Jun 17, 2020·Expert Opinion on Therapeutic Targets·Ravindra N SinghNatalia N Singh
Sep 16, 2020·Pharmacological Reviews·Ai-Ming YuMei-Juan Tu
Apr 29, 2020·International Journal of Molecular Sciences·Siran ZhuGracjan Michlewski
Nov 2, 2019·MedChemComm·Eric ValeurAlleyn T Plowright
Aug 3, 2019·NeoReviews·Lainie Friedman Ross, Jennifer M Kwon
Nov 18, 2020·Chemical Communications : Chem Comm·Amanda E Hargrove
Jan 28, 2021·Annual Review of Medicine·Bhavya RaviCharlotte J Sumner
Dec 8, 2020·Neuroscience Insights·Ravindra N SinghNatalia N Singh
Dec 20, 2020·International Journal of Molecular Sciences·Wei ChiuHao-Min Cheng
Feb 4, 2021·Current Opinion in Chemical Biology·Ashley R Julio, Keriann M Backus
Mar 23, 2021·Therapeutic Advances in Neurological Disorders·Alma OsmanovicSusanne Petri
May 1, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Zhichao TangJingxin Wang
Apr 25, 2021·Seminars in Pediatric Neurology·Stefan NicolauJerry R Mendell
May 13, 2021·Cell Reports·Nikki M McCormackBarrington G Burnett
Jun 2, 2021·Journal of Medicinal Chemistry·Farzad Zamani, Takayoshi Suzuki
Apr 27, 2021·Annual Review of Chemical and Biomolecular Engineering·Walter ThavarajahJulius B Lucks
Jun 9, 2021·Nature Communications·Dadi GaoSusan A Slaugenhaupt
Jun 19, 2021·ACS Medicinal Chemistry Letters·Jingru Xie, Aaron T Frank
Dec 29, 2020·Archives de pédiatrie : organe officiel de la Sociéte française de pédiatrie·S Lefebvre, C Sarret
Jun 29, 2021·Médecine sciences : M/S·Amel Saoudi, Aurélie Goyenvalle
Jun 19, 2021·ACS Medicinal Chemistry Letters·Amanda L Garner, Stevan W Djuric
Apr 25, 2020·Journal of Medicinal Chemistry·Lewis D PenningtonIngo Muegge
Mar 28, 2020·Journal of Medicinal Chemistry·Matthew G CostalesMatthew D Disney
Aug 18, 2020·ACS Chemical Biology·Herschel MukherjeeJennifer C Petter
Aug 28, 2021·International Journal of Molecular Sciences·Eric William OttesenRavindra Narayan Singh
Oct 1, 2021·Journal of Medicinal Chemistry·Murugaiah A M Subbaiah, Nicholas A Meanwell

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