Small molecule drug for myotonic dystrophy type 1 (DM1)
May 12, 2022
Background / Context / Abstract:
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.
JM642 is newly developed by researchers. This new small molecule targeting expanded CUG repeat RNA recover splicing defects in DM1. JM642 is the dimeric form of 1,3-diaminoisoquinoline derivative and have a significant effect on the binding to the CUG repeat RNA.
New Chemical Entity
High binding ability to CUG repeat
Potential Applications / Potential Markets:
Therapeutic drug for myotonic dystrophy type 1
State of Development / Opportunity / Seeking:
・Available for exclusive and non-exclusive licensing
・Exclusive/non-exclusive evaluation for defined period (set up for options)
1. Development partner
Chemistry Europe Website：
PCT applied in Japanese