Plitidepsin (also known as dehydrodidemnin B, marketed by PharmaMar, S.A. under the trade name Aplidin) is a chemical compound extracted from the ascidianAplidium albicans.[1] It is currently undergoing clinical trial testing. It is a member of the class of compounds known as didemnins.
Plitidepsin is a cyclic depsipeptide, meaning it is a cyclicpeptide in which there is one or more ester bond in place of one or more of a peptide bond. Its chemical structure is very close to that of didemnin B, the only difference being that the lactate residue in didemnin B is present in the oxidizedpyruvate version.[citation needed]
Pharmacological activityedit
Like all didemnin compounds, plitidepsin exhibits antitumor, antiviral and immunosuppressive activities. It shows promise in shrinking tumors in pancreatic, stomach, bladder, and prostate cancers.[2][3]
Plitidepsin inhibits the human protein eEF1A which has potential interactions with multiple coronavirus proteins. Plitidepsin possesses antiviral activity against SARS-CoV-2 in vitro and in an in vivo mouse model.[4]
Marketing authorisation statusedit
European Unionedit
In July 2003, plitidepsin was granted orphan drug status by the European Medicines Agency for treating acute lymphoblastic leukemia.[5] On 14 December 2017, EMA's Committee for Medicinal Products for Human Use adopted a negative opinion, recommending the refusal of the marketing authorisation for the treatment of multiple myeloma. PharmaMar requested a re-examination of the initial opinion. After a re-examination of the opinion, the refusal of the marketing authorisation was confirmed on 22 March 2018. The CHMP was of the opinion that the benefits of Aplidin did not outweigh its risks. Improvement in overall survival was not sufficiently demonstrated, and severe side effects were reported more frequently with the combination of Aplidin and dexamethasone than with dexamethasone alone. On 1 October 2018, PharmaMar appealed against this decision, alleging a lack of impartiality on the part of certain members of the Scientific Advisory Group that had advised the CHMP. On 28 October 2020, the General Court upheld PharmaMar's appeal and annulled the decision refusing marketing authorisation for Aplidin, and the European Commission then returned the application for Aplidin to the EMA.[6]
Australiaedit
In Australia plitidepsin was approved in December 2018, in combination with dexamethasone, for the treatment of patients with relapsed and refractory multiple myeloma who have received at least three prior treatment regimens, including both a proteasome inhibitor and an immunomodulator. It may be used after two prior lines of therapy if refractory and/or intolerant to both a proteasome inhibitor and an immunomodulator.[7]
In 2016, early results in a small phase I trial for multiple myeloma were announced.[8]
Referencesedit
^Newman DJ, Cragg GM (August 2004). "Marine natural products and related compounds in clinical and advanced preclinical trials". Journal of Natural Products. 67 (8): 1216–38. doi:10.1021/np040031y. PMID 15332835.
^Garrison T (2002). Oceanography: An Invitation to Marine Science (4th ed.). United States: Brooks/Cole. p. 98.
^ abAdrio J, Cuevas C, Manzanares I, Joullié MM (July 2007). "Total synthesis and biological evaluation of tamandarin B analogues". The Journal of Organic Chemistry. 72 (14): 5129–38. doi:10.1021/jo070412r. PMID 17555353.
^White KM, Rosales R, Yildiz S, Kehrer T, Miorin L, Moreno E, et al. (January 2021). "Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A". Science. 371 (6532): 926–931. Bibcode:2021Sci...371..926W. doi:10.1126/science.abf4058. PMC7963220. PMID 33495306.
^"Public Summary of Positive Opinion for Orphan Designation of Aplidine for the Treatment of Acute Lymphoblastic Leukaemia" (PDF). European Medicines Agency (EMA). 1 September 2011.
^"AusPAR: Plitidepsin". Australian Public Assessment Report. 8 July 2019.
^Kailes S (June 2016). "ASCO: Plitidepsin Shows Activity in Multiple Myeloma". MedPage Today.
April 15, 2024
plitidepsin, also, known, dehydrodidemnin, marketed, pharmamar, under, trade, name, aplidin, chemical, compound, extracted, from, ascidian, aplidium, albicans, currently, undergoing, clinical, trial, testing, member, class, compounds, known, didemnins, namessy. Plitidepsin also known as dehydrodidemnin B marketed by PharmaMar S A under the trade name Aplidin is a chemical compound extracted from the ascidian Aplidium albicans 1 It is currently undergoing clinical trial testing It is a member of the class of compounds known as didemnins Plitidepsin NamesSystematic IUPAC name 2S N 1R 1 3S 6R 7S 10R 11S 15S 17S 20S 25aS 10 2S Butan 2 yl 11 hydroxy 3 4 methoxyphenyl methyl 2 6 17 trimethyl 20 2 methylpropyl 1 4 8 13 16 18 21 heptaoxo 15 propan 2 yl docosahydro 15H pyrrolo 2 1 d 10 19 1 4 7 14 dioxatetraazacyclotricosin 7 yl carbamoyl 3 methylbutyl N methyl 1 2 oxopropanoyl pyrrolidine 2 carboxamideOther names Aplidine Dehydrodidemnin B Aplidin N 1 1 2 Dioxopropyl L prolyl didemnin AIdentifiersCAS Number 137219 37 5 Y3D model JSmol Interactive imageChEBI CHEBI 90205ChEMBL ChEMBL451930ChemSpider 26001665 YDrugBank DB04977KEGG D11032PubChem CID 9812534UNII Y76ID234HW YCompTox Dashboard EPA DTXSID0040418InChI InChI 1S C59H91N7O14 c1 15 35 8 50 47 69 30 49 71 80 53 34 6 7 52 72 37 10 54 73 60 41 26 32 2 3 58 77 65 24 16 18 42 65 48 70 31 63 12 44 29 39 20 22 40 79 14 23 21 39 46 68 28 36 9 51 56 75 61 50 62 55 74 45 27 33 4 5 64 13 59 78 43 19 17 25 66 43 57 76 38 11 67 h20 23 32 37 41 45 47 50 51 53 69H 15 19 24 31H2 1 14H3 H 60 73 H 61 75 H 62 74 t35 36 37 41 42 43 44 45 47 50 51 53 m0 s1 YKey RZFJKZZAZSUBCF VETSTYKFSA N YSMILES O C C H NC C H C C C H OC C C H O C H NC C H NC C H N C C H 1N C C C O O CCC1 O C CC C C O C H C OC C H CC2 CC C OC C C2 N3C O O C H C CC O C C C O O CC C C N4 C H C3 O CCC4PropertiesChemical formula C 57H 87N 7O 15Molar mass 1110 357 g mol 1PharmacologyATC code L01XX57 WHO Except where otherwise noted data are given for materials in their standard state at 25 C 77 F 100 kPa Y verify what is Y N Infobox references Contents 1 Chemical structure 2 Pharmacological activity 3 Marketing authorisation status 3 1 European Union 3 2 Australia 4 Clinical trials 5 ReferencesChemical structure editPlitidepsin is a cyclic depsipeptide meaning it is a cyclic peptide in which there is one or more ester bond in place of one or more of a peptide bond Its chemical structure is very close to that of didemnin B the only difference being that the lactate residue in didemnin B is present in the oxidized pyruvate version citation needed Pharmacological activity editLike all didemnin compounds plitidepsin exhibits antitumor antiviral and immunosuppressive activities It shows promise in shrinking tumors in pancreatic stomach bladder and prostate cancers 2 3 Plitidepsin inhibits the human protein eEF1A which has potential interactions with multiple coronavirus proteins Plitidepsin possesses antiviral activity against SARS CoV 2 in vitro and in an in vivo mouse model 4 Marketing authorisation status editEuropean Union edit In July 2003 plitidepsin was granted orphan drug status by the European Medicines Agency for treating acute lymphoblastic leukemia 5 On 14 December 2017 EMA s Committee for Medicinal Products for Human Use adopted a negative opinion recommending the refusal of the marketing authorisation for the treatment of multiple myeloma PharmaMar requested a re examination of the initial opinion After a re examination of the opinion the refusal of the marketing authorisation was confirmed on 22 March 2018 The CHMP was of the opinion that the benefits of Aplidin did not outweigh its risks Improvement in overall survival was not sufficiently demonstrated and severe side effects were reported more frequently with the combination of Aplidin and dexamethasone than with dexamethasone alone On 1 October 2018 PharmaMar appealed against this decision alleging a lack of impartiality on the part of certain members of the Scientific Advisory Group that had advised the CHMP On 28 October 2020 the General Court upheld PharmaMar s appeal and annulled the decision refusing marketing authorisation for Aplidin and the European Commission then returned the application for Aplidin to the EMA 6 Australia edit In Australia plitidepsin was approved in December 2018 in combination with dexamethasone for the treatment of patients with relapsed and refractory multiple myeloma who have received at least three prior treatment regimens including both a proteasome inhibitor and an immunomodulator It may be used after two prior lines of therapy if refractory and or intolerant to both a proteasome inhibitor and an immunomodulator 7 Clinical trials editAs of 2007 it was undergoing multicenter phase II clinical trials 3 In 2016 early results in a small phase I trial for multiple myeloma were announced 8 References edit Newman DJ Cragg GM August 2004 Marine natural products and related compounds in clinical and advanced preclinical trials Journal of Natural Products 67 8 1216 38 doi 10 1021 np040031y PMID 15332835 Garrison T 2002 Oceanography An Invitation to Marine Science 4th ed United States Brooks Cole p 98 a b Adrio J Cuevas C Manzanares I Joullie MM July 2007 Total synthesis and biological evaluation of tamandarin B analogues The Journal of Organic Chemistry 72 14 5129 38 doi 10 1021 jo070412r PMID 17555353 White KM Rosales R Yildiz S Kehrer T Miorin L Moreno E et al January 2021 Plitidepsin has potent preclinical efficacy against SARS CoV 2 by targeting the host protein eEF1A Science 371 6532 926 931 Bibcode 2021Sci 371 926W doi 10 1126 science abf4058 PMC 7963220 PMID 33495306 Public Summary of Positive Opinion for Orphan Designation of Aplidine for the Treatment of Acute Lymphoblastic Leukaemia PDF European Medicines Agency EMA 1 September 2011 Aplidin European Medicines Agency EMA AusPAR Plitidepsin Australian Public Assessment Report 8 July 2019 Kailes S June 2016 ASCO Plitidepsin Shows Activity in Multiple Myeloma MedPage Today Retrieved from https en wikipedia org w index php title Plitidepsin amp oldid 1195115457, wikipedia, wiki, book, books, library,
