Trodusquemine: Difference between revisions
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Aeffenberger (talk | contribs) rewrote lede. existing refs -> citation templates for ease of use, maintenance. →Chemistry: added section. →History: moved content, minor rewrite. →Pharmacology: moved content, needs review (TODO) |
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| DrugBank = DB06333 |
| DrugBank = DB06333 |
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| UNII = KKC12PIF16 |
| UNII = KKC12PIF16 |
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|KEGG=D06252 |
| KEGG = D06252 |
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|ChEMBL=508583 |
| ChEMBL = 508583 |
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| synonyms = MSI-1436 |
| synonyms = MSI-1436 |
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<!-- Chemical and physical data --> |
<!-- Chemical and physical data --> |
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| StdInChIKey = WUJVPODXELZABP-FWJXURDUSA-N |
| StdInChIKey = WUJVPODXELZABP-FWJXURDUSA-N |
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| 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 |
| 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 |
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}} |
}} |
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'''Trodusquemine''' (MSI-1436) is an aminosterol ( |
'''Trodusquemine''' (MSI-1436) is an aminosterol ([[polyamine]] [[steroid]] conjugate) that inhibits [[PTPN1|protein tyrosine phosphatase 1B]] (PTP1B) activity.<ref name="acs"/> The compound exhibits broad-spectrum [[antimicrobial]] activity<ref name="pmid10843574"/> and numerous [[Regeneration (biology)|regenerative]], [[Neuroprotection|neuroprotective]], anti-[[|Atherosclerosis|atherosclerotic]], [[chemotherapy|antitumor]], [[Angiogenesis inhibitor|antiangiogenic]], [[Anti-obesity medication|antiobesity]], and [[anxiolytic]] properties.<ref name="pmid34698757"/> 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.<ref name="pmid35162998"/> |
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== Chemistry == |
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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> |
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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.<ref name="pmid34698757"/> |
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== Pharmacology == |
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Trodusquemine is a non-competitive [[Allosteric regulation|allosteric]] inhibitor of [[PTPN1|protein tyrosine phosphatase 1B]] (PTP1B) with an [[IC50]] value of 1 µmol/L.<ref name="pmid20075852"/> Inhibition of PTP1B prevents dephosphorylation of the [[insulin receptor]], thereby increasing insulin signaling and lowering [[Blood sugar level|blood glucose]].<ref name="pmid35162998"/> Trodusquemine also demonstrates affinity for the [[dopamine transporter]] (IC<sub>50</sub> 0.4 µmol/L) and [[norepinephrine transporter]] (IC<sub>50</sub> 0.7 µmol/L).<ref name="pmid20075852"/> |
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Trodusquemine suppresses appetite, promotes weight loss, and rescues hyperglycemia in genetic mouse models of obesity ([[ob/ob mouse|ob/ob]]) and diabetes ([[Leptin receptor#Animal models|db/db]]).<ref name="pmid11360152"/> |
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⚫ | Although the physiological basis for the healthy lifespan of certain shark species remains unknown, |
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⚫ | Other effects of trodusquemine include amelioration of the metabolic syndrome in mouse models of insulin resistance;<ref name="pmid12086938"/> correction of hepatic steatosis in ob/ob mice;<ref name="pmid15336441"/> reversal of atherosclerosis in [[LDL receptor|LDLR]] knock-out mice;<ref name="pmid28899902"/> inhibition of the growth of malignancy in rodents;<ref name="pmid34794959"/> stimulation of the regeneration of tail-fin and heart muscle in zebrafish;<ref name="pmid29302341"/> stimulation of regenerative repair of myocardial infarction and traumatic limb muscle injury in adult mice;<ref name="pmid29302341"/> prevention of aortic valve calcification in a mouse atheroma model;<ref name="pmid35958694"/> stimulation of T-cell anti-tumor immunity in a mouse model;<ref name="pmid34794959"/> correction of systemic and hepatic inflammation, insulin resistance and hepatic dysfunction in horses suffering from equine metabolic syndrome.<ref name="pmid37020593"/> |
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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;<ref name="pmid31915254"/> reduction in alpha-synuclein aggregation and increase in healthspan and lifespan in a [[Caenorhabditis elegans|''C.elegans'']] model of [[Parkinson's disease]];<ref name="pmid29953201"/> |
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⚫ | |||
⚫ | 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]].<ref name="pmid34698757"/> |
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== History == |
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Trodusquemine was originally isolated from liver extracts of the spiny dogfish (''[[Squalus acanthias]]'').<ref name="pmid10843574"/> 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.<ref name="pmid34698757"/> |
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== References == |
== References == |
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{{reflist |
{{reflist |refs= |
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<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> |
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<ref name="pmid10843574">{{cite journal| author=Rao MN, Shinnar AE, Noecker LA, Chao TL, Feibush B, Snyder B | display-authors=etal| title=Aminosterols from the dogfish shark Squalus acanthias. | journal=J Nat Prod | year= 2000 | volume= 63 | issue= 5 | pages= 631-5 | pmid=10843574 | doi=10.1021/np990514f}} </ref> |
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<ref name="pmid11360152">{{cite journal| author=Zasloff M, Williams JI, Chen Q, Anderson M, Maeder T, Holroyd K | display-authors=etal| title=A spermine-coupled cholesterol metabolite from the shark with potent appetite suppressant and antidiabetic properties. | journal=Int J Obes Relat Metab Disord | year= 2001 | volume= 25 | issue= 5 | pages= 689-97 | pmid=11360152 | doi=10.1038/sj.ijo.0801599}} </ref> |
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<ref name="pmid34698757">{{cite journal| author=Limbocker R, Errico S, Barbut D, Knowles TPJ, Vendruscolo M, Chiti F | display-authors=etal| title=Squalamine and trodusquemine: two natural products for neurodegenerative diseases, from physical chemistry to the clinic. | journal=Nat Prod Rep | year= 2022 | volume= 39 | issue= 4 | pages= 742-753 | pmid=34698757 | doi=10.1039/d1np00042j}} </ref> |
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<ref name="pmid35162998">{{cite journal| author=Kazakova O, Giniyatullina G, Babkov D, Wimmer Z| title=From Marine Metabolites to the Drugs of the Future: Squalamine, Trodusquemine, Their Steroid and Triterpene Analogues. | journal=Int J Mol Sci | year= 2022 | volume= 23 | issue= 3 | pages= | pmid=35162998 | doi=10.3390/ijms23031075 | pmc=8834734}} </ref> |
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<ref name="pmid20075852">{{cite journal| author=Lantz KA, Hart SG, Planey SL, Roitman MF, Ruiz-White IA, Wolfe HR | display-authors=etal| title=Inhibition of PTP1B by trodusquemine (MSI-1436) causes fat-specific weight loss in diet-induced obese mice. | journal=Obesity (Silver Spring) | year= 2010 | volume= 18 | issue= 8 | pages= 1516-23 | pmid=20075852 | doi=10.1038/oby.2009.444}}</ref> |
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<ref name="pmid12086938">{{cite journal| author=Ahima RS, Patel HR, Takahashi N, Qi Y, Hileman SM, Zasloff MA| title=Appetite suppression and weight reduction by a centrally active aminosterol. | journal=Diabetes | year= 2002 | volume= 51 | issue= 7 | pages= 2099-104 | pmid=12086938 | doi=10.2337/diabetes.51.7.2099}}</ref> |
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<ref name="pmid15336441">{{cite journal| author=Takahashi N, Qi Y, Patel HR, Ahima RS| title=A novel aminosterol reverses diabetes and fatty liver disease in obese mice. | journal=J Hepatol | year= 2004 | volume= 41 | issue= 3 | pages= 391-8 | pmid=15336441 | doi=10.1016/j.jhep.2004.05.006}} </ref> |
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<ref name="pmid28899902">{{cite journal| author=Thompson D, Morrice N, Grant L, Le Sommer S, Lees EK, Mody N | display-authors=etal| title=Pharmacological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in the LDLR-/- mouse model of atherosclerosis. | journal=Clin Sci (Lond) | year= 2017 | volume= 131 | issue= 20 | pages= 2489-2501 | pmid=28899902 | doi=10.1042/CS20171066 | pmc=6365594}}</ref> |
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<ref name="pmid34794959">{{cite journal| author=Wiede F, Lu KH, Du X, Zeissig MN, Xu R, Goh PK | display-authors=etal| title=PTP1B Is an Intracellular Checkpoint that Limits T-cell and CAR T-cell Antitumor Immunity. | journal=Cancer Discov | year= 2022 | volume= 12 | issue= 3 | pages= 752-773 | pmid=34794959 | doi=10.1158/2159-8290.CD-21-0694 | pmc=8904293 }} </ref> |
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<ref name="pmid29302341">{{cite journal| author=Smith AM, Maguire-Nguyen KK, Rando TA, Zasloff MA, Strange KB, Yin VP| title=The protein tyrosine phosphatase 1B inhibitor MSI-1436 stimulates regeneration of heart and multiple other tissues. | journal=NPJ Regen Med | year= 2017 | volume= 2 | issue= | pages= 4 | pmid=29302341 | doi=10.1038/s41536-017-0008-1 | pmc=5677970}}</ref> |
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<ref name="pmid35958694">{{cite journal| author=Liu F, Chen J, Hu W, Gao C, Zeng Z, Cheng S | display-authors=etal |title=PTP1B Inhibition Improves Mitochondrial Dynamics to Alleviate Calcific Aortic Valve Disease Via Regulating OPA1 Homeostasis |journal=JACC Basic Transl Sci | year= 2022 | volume= 7 | issue= 7 | pages= 697-712 | pmid=35958694 | doi=10.1016/j.jacbts.2022.03.002 | pmc=9357565}}</ref> |
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<ref name="pmid37020593">{{cite journal| author=Bourebaba L, Serwotka-Suszczak A, Pielok A, Sikora M, Mularczyk M, Marycz K| title=The PTP1B inhibitor MSI-1436 ameliorates liver insulin sensitivity by modulating autophagy, ER stress and systemic inflammation in Equine metabolic syndrome affected horses. | journal=Front Endocrinol (Lausanne) | year= 2023 | volume= 14 | issue= | pages= 1149610 | pmid=37020593 | doi=10.3389/fendo.2023.1149610 | pmc=10067883 }}</ref> |
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<ref name="pmid31915254">{{cite journal| author=Ricke KM, Cruz SA, Qin Z, Farrokhi K, Sharmin F, Zhang L | display-authors=etal| title=Neuronal Protein Tyrosine Phosphatase 1B Hastens Amyloid β-Associated Alzheimer's Disease in Mice. | journal=J Neurosci | year= 2020 | volume= 40 | issue= 7 | pages= 1581-1593 | pmid=31915254 | doi=10.1523/JNEUROSCI.2120-19.2019 | pmc=7044730}}</ref> |
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<ref name="pmid29953201">{{cite journal| author=Perni M, Flagmeier P, Limbocker R, Cascella R, Aprile FA, Galvagnion C | display-authors=etal| title=Multistep Inhibition of α-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine. | journal=ACS Chem Biol | year= 2018 | volume= 13 | issue= 8 | pages= 2308-2319 | pmid=29953201 | doi=10.1021/acschembio.8b00466 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29953201 }} </ref> |
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<ref name="cen2015">{{cite web |title=Helping Brains Relieve Anxiety |last=Torrice |first=Michael |date=March 6, 2015 |journal=Chemical & Engineering News |volume=93 |issue=10 |publisher=American Chemical Society |url=https://cen.acs.org/articles/93/i10/Helping-Brains-Relieve-Anxiety.html |access-date=2024-05-30}}</ref> |
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}} |
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[[Category:Experimental drugs]] |
[[Category:Experimental drugs]] |
Revision as of 22:06, 30 May 2024
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Clinical data | |
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Other names | MSI-1436 |
Identifiers | |
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CAS Number | |
PubChem CID | |
DrugBank | |
ChemSpider | |
UNII | |
KEGG | |
ChEMBL | |
CompTox Dashboard (EPA) | |
Chemical and physical data | |
Formula | C37H72N4O5S |
Molar mass | 685.07 g·mol−1 |
3D model (JSmol) | |
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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
- ^ "Molecule of the Week: Trodusquemine". American Chemical Society. April 13, 2015.
- ^ 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) - ^ 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) - ^ 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) - ^ 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) - ^ 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) - ^ 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) - ^ 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) - ^ 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) - ^ 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) - ^ 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) - ^ 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) - ^ 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) - ^ 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) - ^ 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) - ^ Torrice, Michael (March 6, 2015). "Helping Brains Relieve Anxiety". Chemical & Engineering News. American Chemical Society. Retrieved 2024-05-30.