2-Methoxyestradiol

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2-Methoxyestradiol
2-Methoxyestradiol.svg
Clinical data
Synonyms2-Methoxyestra-1,3,5(10)-triene-3,17β-diol
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.164.606 Edit this at Wikidata
Chemical and physical data
FormulaC19H26O3
Molar mass302.408 g/mol g·mol−1
3D model (JSmol)
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2-Methoxyestradiol (2-ME2) is a natural metabolite of estradiol. As an experimental drug candidate, it is being developed under the tradename of Panzem.[1] It prevents the formation of new blood vessels that tumors need in order to grow (angiogenesis), hence it is an angiogenesis inhibitor.[2]

It also acts as a vasodilator.[citation needed]

2-ME2 is derived from estradiol, although it binds poorly (2000-fold lower activational potency) to known estrogen receptors.[3] However, 2-ME2 retains activity as a high-affinity agonist of the GPER (GPR30).[4]

It induces apoptosis in some cancer cell lines.[5]

It has undergone Phase 1 clinical trials against breast cancer.[citation needed]

A phase II trial of 18 advanced ovarian cancer patients reported encouraging results in October 2007.[6]

Preclinical models also suggest that 2-ME2 could also be effective against inflammatory diseases such as rheumatoid arthritis. Several studies have been conducted showing 2-ME2 is a microtubule-inhibitor[7] and effective against prostate cancer in rodents.[citation needed]

As of 2015, all clinical development of 2-ME2 has been suspended or discontinued.[8] This is significantly due to the very poor oral bioavailability of the molecule and also due to its extensive metabolism. Analogues have been developed to overcome these problems, such as the bis-sulfamate derivative known as STX140,[9] an oral anti-tumour agent [10][11] with improved potency, low metabolism and good pharmacokinetic properties.[12]

As well as being a potent inhibitor of steroid sulfatase it exhibits anti-angiogenic activity, induction of cell cycle arrest and apoptosis in human tumour xenografts, with clinical potential for hormone–independent tumours.  Some of this activity stems from tubulin binding at the colchicine site and disruption of interphase microtubules. STX140 is highly active in tumours that are resistant to chemotherapy.[13] 

In xenograft models of breast and prostate cancer complete cures were achieved after oral treatment and drug-resistant tumours also shrank in size after oral treatment.[11] Conventional treatments for hormone-independent cancers targeting tubulin are associated with side effects, such as neurotoxicity, and can only be given infrequently and intravenously. STX140 is more effective on the same tumours, blocks metastatic spread without the peripheral neuropathy associated with current clinical anticancer drugs.[14]

Relative affinities and uterotrophic efficacies of estrogens

Estrogen ER RBA (%) Uterine weight (%)
Control 100
Estradiol 100 506
Estriol 10 468
2-Hydroxyestradiol 24 285
2-Methoxyestradiol 0.05 101
4-Hydroxyestradiol 45 ?
4-Methoxyestradiol 13 260
2-Hydroxyestrone 2 130
2-Methoxyestrone 0.01 ?
4-Hydroxyestrone 11 351
4-Methoxyestrone 0.13 338
Notes: ER (rat uterine cytosol) RBA + estrogenicity (change in rat uterine wet weight) of estrogen metabolites. Sources: See template.

See also[edit]

References[edit]

  1. ^ EntreMed's Product Information Site Archived May 4, 2005, at the Wayback Machine
  2. ^ Pribluda VS, Gubish ER, Lavallee TM, Treston A, Swartz GM, Green SJ (2000). "2-Methoxyestradiol: an endogenous antiangiogenic and antiproliferative drug candidate". Cancer Metastasis Reviews. 19 (1–2): 173–9. doi:10.1023/a:1026543018478. PMID 11191057.
  3. ^ Sibonga JD, Lotinun S, Evans GL, Pribluda VS, Green SJ, Turner RT (March 2003). "Dose-response effects of 2-methoxyestradiol on estrogen target tissues in the ovariectomized rat". Endocrinology. 144 (3): 785–92. doi:10.1210/en.2002-220632. PMID 12586754.
  4. ^ Thekkumkara T, Snyder R, Karamyan VT (2016). "Competitive Binding Assay for the G-Protein-Coupled Receptor 30 (GPR30) or G-Protein-Coupled Estrogen Receptor (GPER)". Methods in Molecular Biology. 1366: 11–7. doi:10.1007/978-1-4939-3127-9_2. ISBN 978-1-4939-3126-2. PMID 26585123.
  5. ^ LaVallee TM, Zhan XH, Johnson MS, Herbstritt CJ, Swartz G, Williams MS, Hembrough WA, Green SJ, Pribluda VS (January 2003). "2-methoxyestradiol up-regulates death receptor 5 and induces apoptosis through activation of the extrinsic pathway". Cancer Research. 63 (2): 468–75. PMID 12543804.
  6. ^ "EntreMed Presents Results for Panzem® NCD Phase 2 Ovarian Cancer Study". Archived from the original on July 17, 2012.
  7. ^ Lakhani NJ, Sarkar MA, Venitz J, Figg WD (February 2003). "2-Methoxyestradiol, a promising anticancer agent". Pharmacotherapy. 23 (2): 165–72. doi:10.1592/phco.23.2.165.32088. PMID 12587805.
  8. ^ "2-Methoxyestradiol - CASI Pharmaceuticals". Adis Insight. Retrieved 2 March 2017.
  9. ^ Potter, B V L (2018). "SULFATION PATHWAYS: Steroid Sulphatase Inhibition by Aryl Sulphamates: Clinical Progress, Mechanism and Future Prospects". J. Mol. Endocrinol. 61 (2): T233–T252. doi:10.1530/JME-18-0045. PMID 29618488.
  10. ^ Leese, M P, LeBlond B, Smith A, Newman S P, Di Fiore A, De Simone G, Supuran C T, Purohit A, Reed M J & Potter B V L (2006). "2-Substituted estradiol bis-sulfamates, multi-targeted anti-tumor agents: Synthesis, in vitro SAR, protein crystallography and in vivo activity". J Med Chem. 49 (26): 7683–7696. doi:10.1021/jm060705x. PMID 17181151 – via doi: 10.1021/jm060705x.
  11. ^ a b Thomas, M P & Potter B V L (2015). "Estrogen O-sulfamates and their analogues: clinical steroid sulfatase inhibitors with broad potential". J Steroid Biochem Mol Biol. 153 (19): 160–169. doi:10.1021/acs.jmedchem.5b00386. PMC 5159624. PMID 25992880 – via doi: 10.1021/acs.jmedchem.5b00386.
  12. ^ Thomas, M P & Potter B V L (2015). "Discovery and Development of the Aryl O-Sulfamate Moiety for Oncology and Women's Health". J Med Chem. 58 (19): 7634–7658. doi:10.1021/acs.jmedchem.5b00386. PMC 5159624. PMID 25992880 – via doi: 10.1021/acs.jmedchem.5b00386.
  13. ^ Newman, S P; Foster, P A; Stengel, C; Day, J M; Ho, Y T; Judde, J-G; Lassalle, M; Prevost, G; Leese, M P; et al. (2008). "STX140 is efficacious in vitro and in vivo in taxane resistant breast carcinoma cells". Clin Cancer Res. 14 (2): 597–606. doi:10.1158/1078-0432.CCR-07-1717. PMID 18223236.
  14. ^ Meyer-Losic, F, Newman S P, Day J M, Reed M J, Kasprzyk P G, Purohit A & Foster P A (2013). "STX140, but not paclitaxel, inhibits mammary tumour initiation and progression in C3(1)/SV40 T/t-antigen transgenic mice". PLOS ONE. 8 (12): e80305. Bibcode:2013PLoSO...880305M. doi:10.1371/journal.pone.0080305. PMC 3855596. PMID 24324595 – via doi: 10.1371/journal.pone.0080305.

External links[edit]