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Discovery of a Small Molecule Probe That Post-Translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy

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Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women’s Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, United States
Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
§ Department of Veterinary Pathobiology, Bond Life Sciences Center, University of Missouri, Columbia, Missouri 65201, United States
Department of Anatomy, Physiology and Genetics, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, United States
*Phone: 617-768-8640. E-mail: [email protected]
Cite this: J. Med. Chem. 2017, 60, 11, 4594–4610
Publication Date (Web):May 8, 2017
https://doi.org/10.1021/acs.jmedchem.6b01885
Copyright © 2017 American Chemical Society
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Abstract

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Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. We previously developed a high-throughput assay that employs an SMN2-luciferase reporter allowing identification of compounds that act transcriptionally, enhance exon recognition, or stabilize the SMN protein. We describe optimization and characterization of an analog suitable for in vivo testing. Initially, we identified analog 4m that had good in vitro properties but low plasma and brain exposure in a mouse PK experiment due to short plasma stability; this was overcome by reversing the amide bond and changing the heterocycle. Thiazole 27 showed excellent in vitro properties and a promising mouse PK profile, making it suitable for in vivo testing. This series post-translationally stabilizes the SMN protein, unrelated to global proteasome or autophagy inhibition, revealing a novel therapeutic mechanism that should complement other modalities for treatment of SMA.

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Cited By


This article is cited by 9 publications.

  1. Yonghua Liu, Jianrui Li, Yuxi Gu, Ling Ma, Shan Cen, Zonggen Peng, Laixing Hu. Synthesis and structure-activity relationship study of new biaryl amide derivatives and their inhibitory effects against hepatitis C virus. European Journal of Medicinal Chemistry 2022, 228 , 114033. https://doi.org/10.1016/j.ejmech.2021.114033
  2. Vincent L. Revil‐Baudard, Samir Z. Zard. A Practical Route to Cyclobutanols and Fluorocyclobutanes. Helvetica Chimica Acta 2021, 104 (9) https://doi.org/10.1002/hlca.202100106
  3. Timothy L. Foley, Woodrow Burchett, Qiuxia Chen, Mark E. Flanagan, Brendon Kapinos, Xianyang Li, Justin I. Montgomery, Anokha S. Ratnayake, Hongyao Zhu, Marie-Claire Peakman. Selecting Approaches for Hit Identification and Increasing Options by Building the Efficient Discovery of Actionable Chemical Matter from DNA-Encoded Libraries. SLAS Discovery 2021, 26 (2) , 263-280. https://doi.org/10.1177/2472555220979589
  4. Anne Rietz, Kevin J Hodgetts, Hrvoje Lusic, Kevin M Quist, Erkan Y Osman, Christian L Lorson, Elliot J Androphy. Short-duration splice promoting compound enables a tunable mouse model of spinal muscular atrophy. Life Science Alliance 2021, 4 (1) , e202000889. https://doi.org/10.26508/lsa.202000889
  5. Alexandra Kamlah, Franz Bracher. A Novel Approach to Highly Substituted β‐Carbolines via Reductive Ring Transformation of 2‐Acyl‐3‐isoxazolylindoles. European Journal of Organic Chemistry 2020, 2020 (18) , 2708-2719. https://doi.org/10.1002/ejoc.202000230
  6. E. Y. Osman, A. Rietz, R. A. Kline, J. J. Cherry, K. J. Hodgetts, C. L. Lorson, E. J. Androphy. Intraperitoneal delivery of a novel drug‐like compound improves disease severity in severe and intermediate mouse models of Spinal Muscular Atrophy. Scientific Reports 2019, 9 (1) https://doi.org/10.1038/s41598-018-38208-9
  7. Prabhakar Singh, Arup Dalal, Srinivasarao Arulananda Babu. Palladium(II)‐Catalyzed Sp 3 /Sp 2 γ ‐ and δ ‐C‐H Functionalization of Aryl Amines using 5‐Methylisoxazole‐3‐Carboxamide as Directing Group. Asian Journal of Organic Chemistry 2019, 8 (6) , 877-886. https://doi.org/10.1002/ajoc.201900132
  8. Jing Leng, Hua-Li Qin. 1-Bromoethene-1-sulfonyl fluoride (1-Br-ESF), a new SuFEx clickable reagent, and its application for regioselective construction of 5-sulfonylfluoro isoxazoles. Chemical Communications 2018, 54 (35) , 4477-4480. https://doi.org/10.1039/C8CC00986D
  9. Sungwoon Choi, Alyssa N. Calder, Eliza H. Miller, Kierstyn P. Anderson, Dawid K. Fiejtek, Anne Rietz, Hongxia Li, Jonathan J. Cherry, Kevin M. Quist, Xuechao Xing, Marcie A. Glicksman, Gregory D. Cuny, Christian L. Lorson, Elliot A. Androphy, Kevin J. Hodgetts. Optimization of a series of heterocycles as survival motor neuron gene transcription enhancers. Bioorganic & Medicinal Chemistry Letters 2017, 27 (23) , 5144-5148. https://doi.org/10.1016/j.bmcl.2017.10.066

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