Cyclic tetrapeptide HDAC inhibitors as potential therapeutics for spinal muscular atrophy: Screening with iPSC-derived neuronal cells

Bioorg Med Chem Lett. 2017 Aug 1;27(15):3289-3293. doi: 10.1016/j.bmcl.2017.06.027. Epub 2017 Jun 10.


Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder that is caused by inactivating mutations in the Survival of motor neuron 1 (SMN1) gene, resulting in decreased SMN protein expression. Humans possess a paralog gene, SMN2, which contains a splicing defect in exon 7 leading to diminished expression of full-length, fully functional SMN protein. Increasing SMN2 expression has been a focus of therapeutic development for SMA. Multiple studies have reported the efficacy of histone deacetylase inhibitors (HDACi) in this regard. However, clinical trials involving HDACi have been unsatisfactory, possibly because previous efforts to identify HDACi to treat SMA have employed non-neuronal cells as the screening platform. To address this issue, we generated an SMA-patient specific, induced pluripotent stem cell (iPSC) derived neuronal cell line that contains homogenous Tuj1+neurons. We screened a small library of cyclic tetrapeptide HDACi using this SMA neuronal platform and discovered compounds that elevate SMN2 expression by an impressive twofold or higher. These candidates are also capable of forming gems intranuclearly in SMA neurons, demonstrating biological activity. Our study identifies new potential HDACi therapeutics for SMA screened using a disease-relevant SMA neuronal cellular model.

Keywords: Cyclic peptides; HDAC inhibitor; Neurons; Spinal muscular atrophy; iPSC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Drug Evaluation, Preclinical
  • Histone Deacetylase Inhibitors / chemistry*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Muscular Atrophy, Spinal / drug therapy*
  • Muscular Atrophy, Spinal / genetics
  • Neurogenesis
  • Neurons / drug effects*
  • Neurons / metabolism
  • Peptides, Cyclic / chemistry*
  • Peptides, Cyclic / pharmacology*
  • Survival of Motor Neuron 2 Protein / genetics
  • Up-Regulation / drug effects


  • Histone Deacetylase Inhibitors
  • Peptides, Cyclic
  • SMN2 protein, human
  • Survival of Motor Neuron 2 Protein