Trodusquemine: Difference between revisions

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Undid revision 1214862609 by ZASLOFF (talk) Suspected COI; notice added on the new users page.
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I have restored my page on Trodusquemine. Since I am the scientist who has discovered and studied this and related compounds for the past 25 years, I have the expertise to write an article describing the compound. To describe my relationship with Trodusquemine as a "conflict of interest" makes no sense.
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| synonyms = MSI-1436, produlestan<ref name=adis/>
| synonyms = MSI-1436
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'''Trodusquemine''' is an aminosterol (a [[polyamine]]-[[steroid]]) similar to [[squalamine]] that is an allosteric inhibitor of [[protein-tyrosine phosphatase 1B]] (PTP1B).<ref name=acs>{{cite web |url=https://www.acs.org/content/acs/en/molecule-of-the-week/archive/t/trodusquemine.html |title=Molecule of the Week: Trodusquemine |date=April 13, 2015 |publisher=[[American Chemical Society]] }}</ref><ref>{{cite journal | vauthors = Cho H | title = Protein tyrosine phosphatase 1B (PTP1B) and obesity | journal = Vitamins and Hormones | volume = 91 | pages = 405–24 | date = 2013 | pmid = 23374726 | doi = 10.1016/B978-0-12-407766-9.00017-1 | isbn = 9780124077669 }}</ref> 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.<ref name=adis>{{cite web|title=Trodusquemine|url=http://adisinsight.springer.com/drugs/800009018|publisher=AdisInsight|access-date=16 January 2018|language=en}}</ref><ref name=acs/><ref>{{cite news|last1=George|first1=John| name-list-style = vanc | title=Biotech Genaera shutting down: Never brought drug to market|url=https://www.bizjournals.com/philadelphia/stories/2009/04/27/daily31.html|work=Philadelphia Business Journal|date=April 29, 2009}}</ref>
'''Trodusquemine''' is an aminosterol (a [[polyamine]]-[[steroid]]) that is an allosteric inhibitor of [[protein-tyrosine phosphatase 1B]] (PTP1B).<ref name=acs>{{cite web |url=https://www.acs.org/content/acs/en/molecule-of-the-week/archive/t/trodusquemine.html |title=Molecule of the Week: Trodusquemine |date=April 13, 2015 |publisher=[[American Chemical Society]] }}</ref>. It was isolated from the liver of the [[dogfish shark]] by Michael Zasloff and colleagues in 2000 <ref> PMID=11360152 </ref> and underwent three Phase 1 studies as a treatment for diabetes and obesity <ref> PMID=34698757 </ref>, and despite safety and signals of efficacy, development was discontinued because it could only be formulated for intravenous use.


Trodusquemine was discovered in a search for antimicrobial compounds supporting the innate immune system <ref> PMID=34698757 </ref>. The search was motivated by the hypothesis that the surprising degree of immunity exhibited by certain animals could be due to the presence of endogenous antimicrobial compounds. The dogfish shark fell into that category. Sharks have an adaptive immune system that responds too slowly to defend against most bacterial or viral infections so one might imagine that these animals would be relatively short lived <ref> PMID=15688348 </ref>. Surprisingly, the dogfish enjoys a healthy lifespan with an age limit of at least 100 years <ref> Squalua Acanthias.Convention on the conservation of migratory species of wild animals 2008 </ref>. In fact, another member of the Squaliformes, the [[Greenland shark]], is the longest living vertebrate with a male life span of at least 392 (+/- 120) years <ref> PMID=27516602 </ref>.
Trodusquemine and some other drug assets were sold to Ohr Pharmaceutical for $200,000 by Genaera's liquidator.<ref>{{cite web|title=Ohr Pharmaceutical 10-K for the fiscal year ended September 30, 2009|url=https://www.sec.gov/Archives/edgar/data/1173281/000135448810000035/ohrp_10k.htm|publisher=Ohr via SEC Edgar|page=11|date=January 8, 2010}}</ref> 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.<ref>{{cite news|title=Clinical trials for DepYMed|url=http://www.innovateli.com/clinical-trials-for-depymed/|work=Innovate Long Island|date=17 March 2015}}</ref> As of 2017, Depymed was running a Phase I clinical trial of the drug.<ref name=adis/>
Trodusquemine has been shown to exert its effects by targeting specific centers in the brain <ref> PMID=12086938 </ref>.

The therapeutic effects of Trodusquemine demonstrated in animals include amelioration of the metabolic syndrome in mouse models of insulin resistance <ref> PMID=12086938 </ref>; correction of hepatic steatosis in obese (ob/ob) mice <ref> PMID=15336441 </ref>; reversal of atherosclerosis in LDLR knock-out mice <ref> PMID=28899902 </ref>; inhibition of the growth of malignancy in rodents <ref> PMID=34794959 </ref>; stimulation of the regeneration of tail-fin and heart muscle in zebrafish <ref> PMID=29302341 </ref>; stimulation of regenerative repair of myocardial infarction and traumatic limb muscle injury in adult mice <ref> PMID=29302341 </ref>; reversal of memory impairment, normalization of behavior, reduction of neuronal loss and increase in healthspan and lifespan in mouse models of Alzheimer's disease <ref> PMID=31915254 </ref>; reduction in alpha-synuclein aggregation and increase in healthspan and lifespan in a ''C.elegans'' Parkinson's model <ref> PMID=29953201 </ref>; prevention of aortic valve calcification in a mouse atheroma model <ref> PMID=35958694 </ref>; stimulation of T-cell anti-tumor immunity in a mouse model <ref> PMID=34794959 </ref>; correction of systemic and hepatic inflammation, insulin resistance and hepatic dysfunction in horses suffering from equine metabolic syndrome <ref> PMID=37020593 </ref>.

Although the physiological basis for the healthy lifespan of certain shark species remains unknown, Trodusquemine targets well recognized aging associated processes at both the cellular level and in vivo across many species. These observations conducted in different laboratories suggest that Trodusquemine represents a novel, endogenous vertebrate geroprotector.


==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.<ref>{{cite journal | vauthors = Thompson D, Morrice N, Grant L, Le Sommer S, Lees EK, Mody N, Wilson HM, Delibegovic M | display-authors = 6 | title = -/- mouse model of atherosclerosis | journal = Clinical Science | volume = 131 | issue = 20 | pages = 2489–2501 | date = October 2017 | pmid = 28899902 | pmc = 6365594 | doi = 10.1042/CS20171066 | authorlink8 = Mirela Delibegovic }}</ref>


== References ==
== References ==

Revision as of 13:51, 16 April 2024

Trodusquemine
Clinical data
Other namesMSI-1436
Identifiers
  • [(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
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC37H72N4O5S
Molar mass685.07 g·mol−1
3D model (JSmol)
  • 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=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 is an aminosterol (a polyamine-steroid) that is an allosteric inhibitor of protein-tyrosine phosphatase 1B (PTP1B).[1]. It was isolated from the liver of the dogfish shark by Michael Zasloff and colleagues in 2000 [2] and underwent three Phase 1 studies as a treatment for diabetes and obesity [3], and despite safety and signals of efficacy, development was discontinued because it could only be formulated for intravenous use.

Trodusquemine was discovered in a search for antimicrobial compounds supporting the innate immune system [4]. The search was motivated by the hypothesis that the surprising degree of immunity exhibited by certain animals could be due to the presence of endogenous antimicrobial compounds. The dogfish shark fell into that category. Sharks have an adaptive immune system that responds too slowly to defend against most bacterial or viral infections so one might imagine that these animals would be relatively short lived [5]. Surprisingly, the dogfish enjoys a healthy lifespan with an age limit of at least 100 years [6]. In fact, another member of the Squaliformes, the Greenland shark, is the longest living vertebrate with a male life span of at least 392 (+/- 120) years [7]. Trodusquemine has been shown to exert its effects by targeting specific centers in the brain [8].

The therapeutic effects of Trodusquemine demonstrated in animals include amelioration of the metabolic syndrome in mouse models of insulin resistance [9]; correction of hepatic steatosis in obese (ob/ob) mice [10]; reversal of atherosclerosis in LDLR knock-out mice [11]; inhibition of the growth of malignancy in rodents [12]; stimulation of the regeneration of tail-fin and heart muscle in zebrafish [13]; stimulation of regenerative repair of myocardial infarction and traumatic limb muscle injury in adult mice [14]; reversal of memory impairment, normalization of behavior, reduction of neuronal loss and increase in healthspan and lifespan in mouse models of Alzheimer's disease [15]; reduction in alpha-synuclein aggregation and increase in healthspan and lifespan in a C.elegans Parkinson's model [16]; prevention of aortic valve calcification in a mouse atheroma model [17]; stimulation of T-cell anti-tumor immunity in a mouse model [18]; correction of systemic and hepatic inflammation, insulin resistance and hepatic dysfunction in horses suffering from equine metabolic syndrome [19].

Although the physiological basis for the healthy lifespan of certain shark species remains unknown, Trodusquemine targets well recognized aging associated processes at both the cellular level and in vivo across many species. These observations conducted in different laboratories suggest that Trodusquemine represents a novel, endogenous vertebrate geroprotector.


References

  1. ^ "Molecule of the Week: Trodusquemine". American Chemical Society. April 13, 2015.
  2. ^ PMID=11360152
  3. ^ PMID=34698757
  4. ^ PMID=34698757
  5. ^ PMID=15688348
  6. ^ Squalua Acanthias.Convention on the conservation of migratory species of wild animals 2008
  7. ^ PMID=27516602
  8. ^ PMID=12086938
  9. ^ PMID=12086938
  10. ^ PMID=15336441
  11. ^ PMID=28899902
  12. ^ PMID=34794959
  13. ^ PMID=29302341
  14. ^ PMID=29302341
  15. ^ PMID=31915254
  16. ^ PMID=29953201
  17. ^ PMID=35958694
  18. ^ PMID=34794959
  19. ^ PMID=37020593
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