NAV

Plitidepsin

Identification

Generic Name
Plitidepsin
DrugBank Accession Number
DB04977
Background

Aplidine is a peptide found in tunicates which shows promise in shrinking tumors in pancreatic, stomach, bladder, and prostate cancers. The specific marine organism is Aplidium albicans. Aplidine is also of interest as a potential treatment for some leukemias.

Type
Small Molecule
Groups
Investigational
Structure
Similar Structures
Weight
Average: 1110.357
Monoisotopic: 1109.626015129
Chemical Formula
C57H87N7O15
Synonyms
  • Dehydrodidemnin B
  • Plitidepsin
  • Plitidepsina
  • Plitidepsine
  • Plitidepsium
External IDs
  • NSC638719
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Pharmacology

Indication

Intended for the treatment of various forms of cancer.

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Not Available

Mechanism of action

Plitidepsin has antineoplastic activity which stems from plitidepsin's ability to inhibit cell growth and induce apoptosis.8 Plitidepsin's primary intracellular target is the eukaryotic elongation factor 1A2 (eEF1A2).8,7 It also inhibits the growth and induces apoptosis in MOLT-4 cells by inhibiting VEGF secretion, which blocks the VEGF/VEGFR-1 autocrine loop that is required for the growth of the MOLT-4 cells.1,8

Through inhibition of eEF1A, plitidepsin also demonstrated antiviral activity against SARS-CoV-2.8

The exact mechanism of action is not fully understood and plitidepsin may have multiple modes of action.

TargetActionsOrganism
UElongation factor 1-alpha 2Not AvailableHumans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Hepatic

Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
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interactions in your software
AbataceptThe metabolism of Plitidepsin can be increased when combined with Abatacept.
AcetaminophenThe metabolism of Plitidepsin can be decreased when combined with Acetaminophen.
AdalimumabThe metabolism of Plitidepsin can be increased when combined with Adalimumab.
AmbroxolThe risk or severity of methemoglobinemia can be increased when Plitidepsin is combined with Ambroxol.
AmiodaroneThe metabolism of Plitidepsin can be decreased when combined with Amiodarone.
Food Interactions
Not Available

Products

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International/Other Brands
Aplidin / Aplidine

Categories

ATC Codes
L01XX57 — Plitidepsin
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as cyclic depsipeptides. These are natural or synthetic compounds having sequences of amino and hydroxy carboxylic acid residues (usually α-amino and α-hydroxy acids) connected in a ring. The residues are commonly but not necessarily regularly alternating.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Peptidomimetics
Sub Class
Depsipeptides
Direct Parent
Cyclic depsipeptides
Alternative Parents
Leucine and derivatives / Macrolide lactams / Macrolactams / N-acyl-alpha amino acids and derivatives / Proline and derivatives / Alpha amino acid esters / Alpha amino acid amides / Methoxybenzenes / Pyrrolidinecarboxamides / N-acylpyrrolidines
show 20 more
Substituents
1,3-dicarbonyl compound / Alcohol / Alkyl aryl ether / Alpha-acyloxy ketone / Alpha-amino acid amide / Alpha-amino acid ester / Alpha-amino acid or derivatives / Anisole / Aromatic heteropolycyclic compound / Azacycle
show 40 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
Y76ID234HW
CAS number
137219-37-5
InChI Key
UUSZLLQJYRSZIS-LXNNNBEUSA-N
InChI
InChI=1S/C57H87N7O15/c1-15-33(8)46-44(66)29-45(67)79-49(32(6)7)48(68)34(9)50(69)58-39(26-30(2)3)54(73)64-25-17-19-41(64)56(75)62(13)43(28-37-20-22-38(77-14)23-21-37)57(76)78-36(11)47(52(71)59-46)60-51(70)42(27-31(4)5)61(12)55(74)40-18-16-24-63(40)53(72)35(10)65/h20-23,30-34,36,39-44,46-47,49,66H,15-19,24-29H2,1-14H3,(H,58,69)(H,59,71)(H,60,70)/t33-,34-,36+,39-,40-,41-,42+,43-,44-,46+,47-,49-/m0/s1
IUPAC Name
(2R)-N-[(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-1H-pyrrolo[2,1-f]1,15-dioxa-4,7,10,20-tetraazacyclotricosan-7-yl]-4-methyl-2-{N-methyl-1-[(2S)-1-(2-oxopropanoyl)pyrrolidin-2-yl]formamido}pentanamide
SMILES
[H][C@@]12CCCN1C(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)C(=O)[C@@H](OC(=O)C[C@H](O)[C@]([H])(NC(=O)[C@@H](NC(=O)[C@@H](CC(C)C)N(C)C(=O)[C@@H]1CCCN1C(=O)C(C)=O)[C@@H](C)OC(=O)[C@H](CC1=CC=C(OC)C=C1)N(C)C2=O)[C@@H](C)CC)C(C)C

References

General References
  1. Broggini M, Marchini SV, Galliera E, Borsotti P, Taraboletti G, Erba E, Sironi M, Jimeno J, Faircloth GT, Giavazzi R, D'Incalci M: Aplidine, a new anticancer agent of marine origin, inhibits vascular endothelial growth factor (VEGF) secretion and blocks VEGF-VEGFR-1 (flt-1) autocrine loop in human leukemia cells MOLT-4. Leukemia. 2003 Jan;17(1):52-9. [Article]
  2. Depenbrock H, Peter R, Faircloth GT, Manzanares I, Jimeno J, Hanauske AR: In vitro activity of aplidine, a new marine-derived anti-cancer compound, on freshly explanted clonogenic human tumour cells and haematopoietic precursor cells. Br J Cancer. 1998 Sep;78(6):739-44. [Article]
  3. Sparidans RW, Kettenes-van den Bosch JJ, van Tellingen O, Nuyen B, Henrar RE, Jimeno JM, Faircloth G, Floriano P, Rinehart KL, Beijnen JH: Bioanalysis of aplidine, a new marine antitumoral depsipeptide, in plasma by high-performance liquid chromatography after derivatization with trans-4-hydrazino-2-stilbazole. J Chromatogr B Biomed Sci Appl. 1999 Jun 11;729(1-2):43-53. [Article]
  4. Celli N, Gallardo AM, Rossi C, Zucchetti M, D'Incalci M, Rotilio D: Analysis of aplidine (dehydrodidemnin B), a new marine-derived depsipeptide, in rat biological fluids by liquid chromatography-tandem mass spectrometry. J Chromatogr B Biomed Sci Appl. 1999 Aug 20;731(2):335-43. [Article]
  5. Nuijen B, Bouma M, Henrar RE, Floriano P, Jimeno JM, Talsma H, Kettenes-van den Bosch JJ, Heck AJ, Bult A, Beijnen JH: Pharmaceutical development of a parenteral lyophilized formulation of the novel antitumor agent aplidine. PDA J Pharm Sci Technol. 2000 May-Jun;54(3):193-208. [Article]
  6. Brandon EF, Sparidans RW, van Ooijen RD, Meijerman I, Lazaro LL, Manzanares I, Beijnen JH, Schellens JH: In vitro characterization of the human biotransformation pathways of aplidine, a novel marine anti-cancer drug. Invest New Drugs. 2007 Feb;25(1):9-19. [Article]
  7. Delgado-Calle J, Kurihara N, Atkinson EG, Nelson J, Miyagawa K, Galmarini CM, Roodman GD, Bellido T: Aplidin (plitidepsin) is a novel anti-myeloma agent with potent anti-resorptive activity mediated by direct effects on osteoclasts. Oncotarget. 2019 Apr 12;10(28):2709-2721. doi: 10.18632/oncotarget.26831. eCollection 2019 Apr 12. [Article]
  8. Papapanou M, Papoutsi E, Giannakas T, Katsaounou P: Plitidepsin: Mechanisms and Clinical Profile of a Promising Antiviral Agent against COVID-19. J Pers Med. 2021 Jul 16;11(7). pii: jpm11070668. doi: 10.3390/jpm11070668. [Article]
KEGG Compound
C16862
PubChem Compound
9812534
PubChem Substance
175426924
ChemSpider
24687645
ChEBI
90205
ChEMBL
CHEMBL451930
PDBe Ligand
ZIY
Wikipedia
Plitidepsin
PDB Entries
8g5z / 8g60

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
PhaseStatusPurposeConditionsCount
3CompletedTreatmentRelapsed/Refractory Multiple Myeloma (RRMM)1
3TerminatedTreatmentCoronavirus Disease 2019 (COVID‑19) / Covid 19 Infection1
2CompletedTreatmentLeukemias / Lymphoma1
2CompletedTreatmentMultiple Myeloma (MM)1
2CompletedTreatmentMyelofibrosis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0201 mg/mLALOGPS
logP3.07ALOGPS
logP3.98Chemaxon
logS-4.7ALOGPS
pKa (Strongest Acidic)10.91Chemaxon
pKa (Strongest Basic)-3.1Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count13Chemaxon
Hydrogen Donor Count4Chemaxon
Polar Surface Area284.74 Å2Chemaxon
Rotatable Bond Count15Chemaxon
Refractivity288.14 m3·mol-1Chemaxon
Polarizability117.17 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption-0.5955
Blood Brain Barrier-0.9925
Caco-2 permeable-0.8093
P-glycoprotein substrateSubstrate0.871
P-glycoprotein inhibitor INon-inhibitor0.5983
P-glycoprotein inhibitor IINon-inhibitor0.6832
Renal organic cation transporterNon-inhibitor0.9272
CYP450 2C9 substrateNon-substrate0.8754
CYP450 2D6 substrateNon-substrate0.8752
CYP450 3A4 substrateSubstrate0.6458
CYP450 1A2 substrateNon-inhibitor0.9633
CYP450 2C9 inhibitorNon-inhibitor0.8868
CYP450 2D6 inhibitorNon-inhibitor0.8675
CYP450 2C19 inhibitorNon-inhibitor0.8931
CYP450 3A4 inhibitorNon-inhibitor0.7351
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9601
Ames testNon AMES toxic0.815
CarcinogenicityNon-carcinogens0.9054
BiodegradationNot ready biodegradable0.8974
Rat acute toxicity2.8308 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9549
hERG inhibition (predictor II)Non-inhibitor0.6708
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0006-3530000092-4180b6f5ab26cea0bdda
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0900-8932000022-dde312e89ce16f8e165e
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0fb9-2920000013-5ee33b99c9e238b39676
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-01ow-6940000028-9657e2400ec6ccf0ec27
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0uka-9510000020-948c0b1c5330628077fe
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-00dr-3940000342-ceeeccf037f6f4f8c415
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-324.45712
predicted
DeepCCS 1.0 (2019)
[M+H]+326.18088
predicted
DeepCCS 1.0 (2019)
[M+Na]+332.50983
predicted
DeepCCS 1.0 (2019)

Targets

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Details1. Elongation factor 1-alpha 2
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
This protein promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis.
Specific Function
Gtp binding
Gene Name
EEF1A2
Uniprot ID
Q05639
Uniprot Name
Elongation factor 1-alpha 2
Molecular Weight
50469.86 Da
References
  1. Papapanou M, Papoutsi E, Giannakas T, Katsaounou P: Plitidepsin: Mechanisms and Clinical Profile of a Promising Antiviral Agent against COVID-19. J Pers Med. 2021 Jul 16;11(7). pii: jpm11070668. doi: 10.3390/jpm11070668. [Article]
  2. Delgado-Calle J, Kurihara N, Atkinson EG, Nelson J, Miyagawa K, Galmarini CM, Roodman GD, Bellido T: Aplidin (plitidepsin) is a novel anti-myeloma agent with potent anti-resorptive activity mediated by direct effects on osteoclasts. Oncotarget. 2019 Apr 12;10(28):2709-2721. doi: 10.18632/oncotarget.26831. eCollection 2019 Apr 12. [Article]

Enzymes

Details1. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Brandon EF, Sparidans RW, van Ooijen RD, Meijerman I, Lazaro LL, Manzanares I, Beijnen JH, Schellens JH: In vitro characterization of the human biotransformation pathways of aplidine, a novel marine anti-cancer drug. Invest New Drugs. 2007 Feb;25(1):9-19. [Article]
Details2. Cytochrome P450 2A6
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Exhibits a high coumarin 7-hydroxylase activity. Can act in the hydroxylation of the anti-cancer drugs cyclophosphamide and ifosphamide. Competent in the metabolic activation of aflatoxin B1. Const...
Gene Name
CYP2A6
Uniprot ID
P11509
Uniprot Name
Cytochrome P450 2A6
Molecular Weight
56501.005 Da
References
  1. Brandon EF, Sparidans RW, van Ooijen RD, Meijerman I, Lazaro LL, Manzanares I, Beijnen JH, Schellens JH: In vitro characterization of the human biotransformation pathways of aplidine, a novel marine anti-cancer drug. Invest New Drugs. 2007 Feb;25(1):9-19. [Article]
Details3. Cytochrome P450 2E1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
References
  1. Brandon EF, Sparidans RW, van Ooijen RD, Meijerman I, Lazaro LL, Manzanares I, Beijnen JH, Schellens JH: In vitro characterization of the human biotransformation pathways of aplidine, a novel marine anti-cancer drug. Invest New Drugs. 2007 Feb;25(1):9-19. [Article]
Details4. Cytochrome P450 4A11
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Leukotriene-b4 20-monooxygenase activity
Specific Function
Catalyzes the omega- and (omega-1)-hydroxylation of various fatty acids such as laurate, myristate and palmitate. Has little activity toward prostaglandins A1 and E1. Oxidizes arachidonic acid to 2...
Gene Name
CYP4A11
Uniprot ID
Q02928
Uniprot Name
Cytochrome P450 4A11
Molecular Weight
59347.31 Da
References
  1. Brandon EF, Sparidans RW, van Ooijen RD, Meijerman I, Lazaro LL, Manzanares I, Beijnen JH, Schellens JH: In vitro characterization of the human biotransformation pathways of aplidine, a novel marine anti-cancer drug. Invest New Drugs. 2007 Feb;25(1):9-19. [Article]

Drug created at October 21, 2007 22:23 / Updated at August 26, 2022 21:50