Small molecule drug for myotonic dystrophy type 1 (DM1)

JM642, New small molecule targeting expanded CUG repeat RNA recover splicing defects in DM1.

Advantage and Core Benefit

  • New Chemical Entity
  • High binding ability to CUG repeat

Technology

Researchers have developed new molecule JM642. JM642 is the dimeric form of 1,3-diaminoisoquinoline derivative. JM642 have a significant effect on the binding to the CUG repeat RNA.

Background

DM1 results from a mutation in the dystrophia myotonia protein kinase (DMPK) gene. In most people, the number of CTG repeats in DMPK gene ranges from 5 to 38, while patients with DM1 have a longer repeat tract. When DMPK containing expanded CTG repeats is copied into RNA, the RNA forms abnormal structures containing extremely long CUG repeats. This RNA binds to and sequesters members of the muscleblind-like family of RNA binding proteins (MB), causing both loss of MB function and retention of the expanded DMPK RNA in the nucleus. Loss of function of this protein contributes substantially to the diverse array of neurologic, muscular, and cardiac abnormalities seen in this disorder and it has been shown in mouse models of DM1 that restoration of MB function reverses DM1 related deficits.

Several studies have shown that binding r(CUG) repeat with small molecules can improve DM1 associated defects. The current hypothesis on the expected therapeutic effects of small molecules in the treatment of DM1 stems from the competitive binding of small molecules with RNA-binding proteins to the aberrantly expanded CUG repeat RNA in the nucleus.

Researchers had reported various types of molecules that bind to r(CUG) repeat and modulate the alternative splicing in DM1 cells. In this project, they revisited 1,3-diaminoisoquinoline derivatives after structure-activity studies on small molecules targeting the r(CUG) repeat.

Data

  • JM642 recover splicing defects of Ldb3 gene in DM1 cell model.
  • JM642 recover splicing defects of Clcn1 and Atp2a1 genes in DM1 mouse model.

Patent and Publication

  • Patents have been applied for.
  • Nakatani, et al., Chem. Eur. J. 2020

Researcher

  • Prof. Kazuhito Nakatani. (Department of Regulatory Bioorganic Chemistry, Osaka University)
  • Dr. Masayuki Nakamori.  (Department of Neurology, Osaka University)

Expectations

We are looking for a company to develop DM1 therapeutics drugs based on our lead compounds. If you hope the feasibility study of JM642, please let us know.

Product No. TT-03279

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