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Trodusquemine

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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 (MSI-1436) is an aminosterol (polyamine steroid conjugate) that inhibits protein tyrosine phosphatase 1B (PTP1B) activity.[1] The compound exhibits broad-spectrum antimicrobial activity[2] and numerous regenerative, neuroprotective, anti-[[|Atherosclerosis|atherosclerotic]], antitumor, antiangiogenic, antiobesity, and anxiolytic properties.[3] Phase 1 clinical trials of trodusquemine have demonstrated good tolerability, but several planned Phase 2 trials were halted due to financial difficulties of the developer.[4]

Chemistry

Trodusquemine is a spermine metabolite of cholesterol. The steroid ring consists of a cholestane with a hydroxyl group at C-7 and sulfate group at C-24; spermine is conjugated to the steroid moiety at C-3. It is structurally similar to squalamine, which features a spermidine moiety instead of spermine.[3]

Pharmacology

Trodusquemine is a non-competitive allosteric inhibitor of protein tyrosine phosphatase 1B (PTP1B) with an IC50 value of 1 µmol/L.[5] Inhibition of PTP1B prevents dephosphorylation of the insulin receptor, thereby increasing insulin signaling and lowering blood glucose.[4] Trodusquemine also demonstrates affinity for the dopamine transporter (IC50 0.4 µmol/L) and norepinephrine transporter (IC50 0.7 µmol/L).[5]

Trodusquemine suppresses appetite, promotes weight loss, and rescues hyperglycemia in genetic mouse models of obesity (ob/ob) and diabetes (db/db).[6] Other effects of trodusquemine include amelioration of the metabolic syndrome in mouse models of insulin resistance;[7] correction of hepatic steatosis in ob/ob mice;[8] reversal of atherosclerosis in LDLR knock-out mice;[9] inhibition of the growth of malignancy in rodents;[10] stimulation of the regeneration of tail-fin and heart muscle in zebrafish;[11] stimulation of regenerative repair of myocardial infarction and traumatic limb muscle injury in adult mice;[11] prevention of aortic valve calcification in a mouse atheroma model;[12] stimulation of T-cell anti-tumor immunity in a mouse model;[10] correction of systemic and hepatic inflammation, insulin resistance and hepatic dysfunction in horses suffering from equine metabolic syndrome.[13]

Demonstrations of trodusquemine's neuroprotective effects include reversal of memory impairment, normalization of behavior, reduction of neuronal loss and increase in healthspan and lifespan in mouse models of Alzheimer's disease;[14] reduction in alpha-synuclein aggregation and increase in healthspan and lifespan in a C.elegans model of Parkinson's disease;[15] Trodusquemine may exert its effects by targeting specific centers in the brain.[7] Trodusquemine may also have anxiolytic properties.[16]

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.[3]

History

Trodusquemine was originally isolated from liver extracts of the spiny dogfish (Squalus acanthias).[2] It was discovered through a search for antimicrobial compounds in Squaliformes, which lack a robust adaptive immune system. It was hypothesized that their innate immunity might be conferred by endogenous production of antimicrobial compounds.[3]

References

  1. ^ "Molecule of the Week: Trodusquemine". American Chemical Society. April 13, 2015.
  2. ^ a b Rao MN, Shinnar AE, Noecker LA, Chao TL, Feibush B, Snyder B; et al. (2000). "Aminosterols from the dogfish shark Squalus acanthias". J Nat Prod. 63 (5): 631–5. doi:10.1021/np990514f. PMID 10843574.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ a b c d Limbocker R, Errico S, Barbut D, Knowles TPJ, Vendruscolo M, Chiti F; et al. (2022). "Squalamine and trodusquemine: two natural products for neurodegenerative diseases, from physical chemistry to the clinic". Nat Prod Rep. 39 (4): 742–753. doi:10.1039/d1np00042j. PMID 34698757.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ a b Kazakova O, Giniyatullina G, Babkov D, Wimmer Z (2022). "From Marine Metabolites to the Drugs of the Future: Squalamine, Trodusquemine, Their Steroid and Triterpene Analogues". Int J Mol Sci. 23 (3). doi:10.3390/ijms23031075. PMC 8834734. PMID 35162998.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  5. ^ a b Lantz KA, Hart SG, Planey SL, Roitman MF, Ruiz-White IA, Wolfe HR; et al. (2010). "Inhibition of PTP1B by trodusquemine (MSI-1436) causes fat-specific weight loss in diet-induced obese mice". Obesity (Silver Spring). 18 (8): 1516–23. doi:10.1038/oby.2009.444. PMID 20075852.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ Zasloff M, Williams JI, Chen Q, Anderson M, Maeder T, Holroyd K; et al. (2001). "A spermine-coupled cholesterol metabolite from the shark with potent appetite suppressant and antidiabetic properties". Int J Obes Relat Metab Disord. 25 (5): 689–97. doi:10.1038/sj.ijo.0801599. PMID 11360152.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ a b Ahima RS, Patel HR, Takahashi N, Qi Y, Hileman SM, Zasloff MA (2002). "Appetite suppression and weight reduction by a centrally active aminosterol". Diabetes. 51 (7): 2099–104. doi:10.2337/diabetes.51.7.2099. PMID 12086938.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Takahashi N, Qi Y, Patel HR, Ahima RS (2004). "A novel aminosterol reverses diabetes and fatty liver disease in obese mice". J Hepatol. 41 (3): 391–8. doi:10.1016/j.jhep.2004.05.006. PMID 15336441.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Thompson D, Morrice N, Grant L, Le Sommer S, Lees EK, Mody N; et al. (2017). "Pharmacological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in the LDLR-/- mouse model of atherosclerosis". Clin Sci (Lond). 131 (20): 2489–2501. doi:10.1042/CS20171066. PMC 6365594. PMID 28899902.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ a b Wiede F, Lu KH, Du X, Zeissig MN, Xu R, Goh PK; et al. (2022). "PTP1B Is an Intracellular Checkpoint that Limits T-cell and CAR T-cell Antitumor Immunity". Cancer Discov. 12 (3): 752–773. doi:10.1158/2159-8290.CD-21-0694. PMC 8904293. PMID 34794959.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ a b Smith AM, Maguire-Nguyen KK, Rando TA, Zasloff MA, Strange KB, Yin VP (2017). "The protein tyrosine phosphatase 1B inhibitor MSI-1436 stimulates regeneration of heart and multiple other tissues". NPJ Regen Med. 2: 4. doi:10.1038/s41536-017-0008-1. PMC 5677970. PMID 29302341.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ Liu F, Chen J, Hu W, Gao C, Zeng Z, Cheng S; et al. (2022). "PTP1B Inhibition Improves Mitochondrial Dynamics to Alleviate Calcific Aortic Valve Disease Via Regulating OPA1 Homeostasis". JACC Basic Transl Sci. 7 (7): 697–712. doi:10.1016/j.jacbts.2022.03.002. PMC 9357565. PMID 35958694.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Bourebaba L, Serwotka-Suszczak A, Pielok A, Sikora M, Mularczyk M, Marycz K (2023). "The PTP1B inhibitor MSI-1436 ameliorates liver insulin sensitivity by modulating autophagy, ER stress and systemic inflammation in Equine metabolic syndrome affected horses". Front Endocrinol (Lausanne). 14: 1149610. doi:10.3389/fendo.2023.1149610. PMC 10067883. PMID 37020593.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  14. ^ Ricke KM, Cruz SA, Qin Z, Farrokhi K, Sharmin F, Zhang L; et al. (2020). "Neuronal Protein Tyrosine Phosphatase 1B Hastens Amyloid β-Associated Alzheimer's Disease in Mice". J Neurosci. 40 (7): 1581–1593. doi:10.1523/JNEUROSCI.2120-19.2019. PMC 7044730. PMID 31915254.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Perni M, Flagmeier P, Limbocker R, Cascella R, Aprile FA, Galvagnion C; et al. (2018). "Multistep Inhibition of α-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine". ACS Chem Biol. 13 (8): 2308–2319. doi:10.1021/acschembio.8b00466. PMID 29953201.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ^ Torrice, Michael (March 6, 2015). "Helping Brains Relieve Anxiety". Chemical & Engineering News. American Chemical Society. Retrieved 2024-05-30.
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