Trodusquemine

Trodusquemine is an aminosterol (a polyamine-steroid) similar to squalamine that is an allosteric inhibitor of protein-tyrosine phosphatase 1B (PTP1B).[2][3] It was isolated from the dogfish shark by scientists at Magainin Pharmaceuticals (subsequently called Genaera) in 2000 and underwent some drug development as a potential treatment for diabetes or obesity, but the company ran out of money and closed in 2009.[1][2][4]

Trodusquemine
Clinical data
Other namesMSI-1436, produlestan[1]
Identifiers
IUPAC name
  • [(3R,6R)-6-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-[3-[4-(3-Aminopropylamino)butylamino]propylamino]-7-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methylheptan-3-yl] hydrogen sulfate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC37H72N4O5S
Molar mass685.07 g·mol−1
3D model (JSmol)
SMILES
  • C[C@H](CC[C@H](C(C)C)OS(=O)(=O)O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2[C@@H](C[C@@H]4[C@@]3(CC[C@@H](C4)NCCCNCCCCNCCCN)C)O)C
InChI
  • InChI=1S/C37H72N4O5S/c1-26(2)34(46-47(43,44)45)13-10-27(3)30-11-12-31-35-32(15-17-37(30,31)5)36(4)16-14-29(24-28(36)25-33(35)42)41-23-9-22-40-20-7-6-19-39-21-8-18-38/h26-35,39-42H,6-25,38H2,1-5H3,(H,43,44,45)/t27-,28-,29+,30-,31+,32+,33-,34-,35+,36+,37-/m1/s1
  • Key:WUJVPODXELZABP-FWJXURDUSA-N

Trodusquemine and some other drug assets were sold to Ohr Pharmaceutical for $200,000 by Genaera's liquidator.[5] In 2014 a company called Depymed was formed based on work done on PTP1B inhibitors at Cold Spring Harbor Laboratory, and it licensed rights to Trodusquemine from Ohr. Depymed wanted to develop it for HER2-positive breast cancer.[6] As of 2017, Depymed was running a Phase I clinical trial of the drug.[1]

Coronary heart disease

British Heart Foundation trials using mice with atherosclerosis which were conducted at the University of Aberdeen suggests a link between atherosclerosis and insulin resistance due to impaired insulin receptor (IR) signalling. Inhibiting the activity of PTP1B, which is the major negative regulator of the insulin receptor appeared to inhibit atherosclerotic plaque formation. The trial mice reportedly had significantly less fatty plaques in their arteries following a single dose of trodusquemine.[7]

References
  1. "Trodusquemine". AdisInsight. Retrieved 16 January 2018.
  2. "Molecule of the Week: Trodusquemine". American Chemical Society. April 13, 2015.
  3. Cho H (2013). "Protein tyrosine phosphatase 1B (PTP1B) and obesity". Vitamins and Hormones. 91: 405–24. doi:10.1016/B978-0-12-407766-9.00017-1. ISBN 9780124077669. PMID 23374726.
  4. George J (April 29, 2009). "Biotech Genaera shutting down: Never brought drug to market". Philadelphia Business Journal.
  5. "Ohr Pharmaceutical 10-K for the fiscal year ended September 30, 2009". Ohr via SEC Edgar. January 8, 2010. p. 11.
  6. "Clinical trials for DepYMed". Innovate Long Island. 17 March 2015.
  7. Thompson D, Morrice N, Grant L, Le Sommer S, Lees EK, Mody N, et al. (October 2017). "-/- mouse model of atherosclerosis". Clinical Science. 131 (20): 2489–2501. doi:10.1042/CS20171066. PMC 6365594. PMID 28899902.
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