MSI-1436, also known as trodusquemine, is a naturally occurring aminosterol that inhibits protein tyrosine phosphatase 1B (PTP1B) by a non-competitive allosteric mechanism. MSI-1436 was originally isolated from the liver of the dogfish shark. PTP1B dephosphorylates and inactivates receptor activated tyrosine kinases. PTP1B deactivates multiple cell signaling pathways that function normally to trigger regeneration. MSI-1436 is a small molecule that inhibits PTP1B and stimulates regeneration in the adult mammalian heart. The small molecule is a drug candidate of the company Novo Biosciences for treating heart disease and Duchenne muscular dystrophy (DMD). A small molecule drug is a substance that is able to enter cells easily and once inside, can affect other molecules. Novo has shown that trodusquemine slows heart and skeletal muscle degeneration in a mouse DMD model.
The structure of MSI-1436 is similar to squalamine. The molecule is found in the amygdala of the mammalian brain. It has been evaluated as an obesity-fighting drug and as an antianxiety drug. Increased PTP1B levels have been shown to disrupt endocannabinoid signaling, causing anxiety. Administering trodusquemine to mice with high PTP1B activity was shown to restore endocannabinoid levels and reduce anxiety.
Researchers at Novo Biosciences presented a paper in 2017 demonstrating the regenerative properties of MSI-1436. MSI-1436 was isolated in a phenotypic screen in zebrafish for small molecules able to stimulate innate tissue repair and regeneration processes. MSI-1436 treatment of adult zebrafish stimulated the rate of regeneration of caudal fin tissue and heart muscle by 2-3 fold and did not show tissue overgrowth or malformation. The administration of MSI-1436 for 4 weeks in adult mice beginning 24 hours after induced cardiac ischemia increased survival, improved heart function, reduced infarct size, reduced ventricular wall thinning and increased cellular proliferation. Treatment of mice with MSI-1436 after induced skeletal muscle injury stimulated satellite cell activation about 2 fold.
Voot Yin, Novo Bioscience’s chief scientific officer was awarded a two-year $1.5 million Small Business Innovation Research grant in 2017 from the National Heart, Lung and Blood Institute, an institute of the National Institutes of Health (NIH), to study trodusquemine in the pig. The pig heart closely resembles that of a human. The drug is being tested as a treatment for acute heart attack and also for chronic heart injury, Duchenne muscular dystrophy, skeletal muscle injury and spinal cord damage.
Phase I and 1b clinical trials with MSI-1436 as potential treatments for obesity and diabetes have shown the molecule to be well tolerated by patients and that MSI-1436 induces metabolic changes consistent with PTP1B inhibition. Doses of MSI-1436 that stimulate tissue regeneration in zebrafish and mice are 5-50 times lower than the maximum well tolerated human dose.
In February, 2019, Yin was awarded a $100,000 pilot grant to study the efficacy of trodusquemine as a regenerative medicine therapy for diabetic kidney disease. Novo will study trodusquemine in mice with kidney abnormalities similar to those in human diabetic nephropathy.
The protein tyrosine phosphatase 1B inhibitor MSI-1436 stimulates regeneration of heart and multiple other tissues
Ashley M. Smith, Katie K. Maguire-Nguyen, Thomas A. Rando, Michael A. Zasloff, Kevin B. Strange & Viravuth P. Yin
npj Regenerative Medicinevolume 2, Article number: 4 (2017)
Regenerative properties of MSI-1436 demonstrated in zebrafish caudal fin and mouse heart and skeletal muscle.
Aminosterols from the Dogfish SharkSqualus acanthias
Meenakshi N. Rao, Ann E. Shinnar, Lincoln A. Noecker, Tessa L., Chao, Binyamin Feibush, Brad SnyderIlya, Sharkansky ,Ani Sarkahian, Xuehai Zhang, Stephen R. Jones, William A. Kinney, Michael Zasloff
J. Nat. Prod. 2000, 635, 631-635
Trodusquemine was one of seven new aminosterols related to squalamine isolated from the liver of the dogfish shark Squalus acathias.