Depatuxizumab mafodotin

Identification

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Name
Depatuxizumab mafodotin
Accession Number
DB11731  (DB12315)
Type
Small Molecule
Groups
Investigational
Description

Depatuxizumab/Denintuzumab mafodotin has been used in trials studying the treatment of Lymphoma, Gliosarcoma, Glioblastoma, Malignant Glioma, Squamous Cell Tumors, and Glioblastoma Multiforme.

Structure
Thumb
Synonyms
  • Denintuzumab mafodotin
External IDs
1399672-02-6 / ABT-414 / SGN-19A / SGN-CD 19A / SGN-CD19A
Categories
UNII
F3R7A4P04N
CAS number
1585973-65-4
Weight
Average: 925.178
Monoisotopic: 924.557207291
Chemical Formula
C49H76N6O11
InChI Key
ORFNVPGICPYLJV-MPEKCWBXSA-N
InChI
InChI=1S/C49H76N6O11/c1-12-32(6)44(37(65-10)29-41(59)54-27-19-22-36(54)45(66-11)33(7)46(60)50-35(49(63)64)28-34-20-15-13-16-21-34)53(9)48(62)42(30(2)3)51-47(61)43(31(4)5)52(8)38(56)23-17-14-18-26-55-39(57)24-25-40(55)58/h13,15-16,20-21,24-25,30-33,35-37,42-45H,12,14,17-19,22-23,26-29H2,1-11H3,(H,50,60)(H,51,61)(H,63,64)/t32-,33+,35-,36-,37+,42-,43-,44-,45?/m0/s1
IUPAC Name
(2S)-2-{[(2R)-3-[(2S)-1-[(3R,4S,5S)-4-[(2S)-2-{[(2S)-2-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-methylhexanamido]-1-hydroxy-3-methylbutylidene]amino}-N,3-dimethylbutanamido]-3-methoxy-5-methylheptanoyl]pyrrolidin-2-yl]-1-hydroxy-3-methoxy-2-methylpropylidene]amino}-3-phenylpropanoic acid
SMILES
[H][C@](C)(CC)[C@]([H])(N(C)C(=O)[C@@]([H])(N=C(O)[C@]([H])(C(C)C)N(C)C(=O)CCCCCN1C(=O)C=CC1=O)C(C)C)[C@@]([H])(CC(=O)N1CCC[C@@]1([H])C([H])(OC)[C@@]([H])(C)C(O)=N[C@@]([H])(CC1=CC=CC=C1)C(O)=O)OC

Pharmacology

Indication

No approved indication.

Pharmacodynamics

Selectively targets cancer cells expressing mutant epidermal growth factor receptor (EGFR) vIII or over expressing wild type EGFR 1. Depatuxizumab mafodotin acts on these cells to inhibit microtuble polymerization thus disrupting mitosis and vesicular trafficking 2

Mechanism of action

Depatuxizumab is a chimeric monoclonal antibody for EGFR which is linked to monomethyl aurastatin F via a maleimidocaproyl linker (mafodotin) 1. Once delivered to the cancer cell, the mafodotin component is able to bind to tubulin and inhibit the exchange of GDP for GTP necessary for the polymerization of tubulin subunits to form microtubules. The inhibition of microtubule polymerization disrupts mitosis and interferes with vesicle trafficking in the cancer cell 3 2.

TargetActionsOrganism
NEpidermal growth factor receptor
antibody
Humans
ATubulin beta chain
nucleotide exchange blocker
Humans
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Depatuxizumab mafodotin.
AbituzumabThe risk or severity of adverse effects can be increased when Depatuxizumab mafodotin is combined with Abituzumab.
AbrilumabThe risk or severity of adverse effects can be increased when Depatuxizumab mafodotin is combined with Abrilumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Depatuxizumab mafodotin.
AdecatumumabThe risk or severity of adverse effects can be increased when Adecatumumab is combined with Depatuxizumab mafodotin.
AducanumabThe risk or severity of adverse effects can be increased when Depatuxizumab mafodotin is combined with Aducanumab.
AfelimomabThe risk or severity of adverse effects can be increased when Afelimomab is combined with Depatuxizumab mafodotin.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Depatuxizumab mafodotin.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Depatuxizumab mafodotin.
AmatuximabThe risk or severity of adverse effects can be increased when Depatuxizumab mafodotin is combined with Amatuximab.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

    Learn more
  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
Not Available

References

General References
  1. Phillips AC, Boghaert ER, Vaidya KS, Mitten MJ, Norvell S, Falls HD, DeVries PJ, Cheng D, Meulbroek JA, Buchanan FG, McKay LM, Goodwin NC, Reilly EB: ABT-414, an Antibody-Drug Conjugate Targeting a Tumor-Selective EGFR Epitope. Mol Cancer Ther. 2016 Apr;15(4):661-9. doi: 10.1158/1535-7163.MCT-15-0901. Epub 2016 Feb 4. [PubMed:26846818]
  2. Waight AB, Bargsten K, Doronina S, Steinmetz MO, Sussman D, Prota AE: Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics. PLoS One. 2016 Aug 12;11(8):e0160890. doi: 10.1371/journal.pone.0160890. eCollection 2016. [PubMed:27518442]
  3. Bai RL, Pettit GR, Hamel E: Binding of dolastatin 10 to tubulin at a distinct site for peptide antimitotic agents near the exchangeable nucleotide and vinca alkaloid sites. J Biol Chem. 1990 Oct 5;265(28):17141-9. [PubMed:2211617]
External Links
PubChem Compound
71300933
PubChem Substance
347828090
ChemSpider
57523411
Wikipedia
Depatuxizumab_mafodotin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentBurkitt's Lymphoma / Follicular Lymphoma (FL) / Lymphoma, Large B-Cell, Diffuse (DLBCL) / Mantle Cell Lymphoma (MCL) / Precursor B-Cell Lymphoblastic Leukemia-Lymphoma1
1CompletedTreatmentBurkitt's Lymphoma / Precursor B-Cell Lymphoblastic Leukemia-Lymphoma1
1CompletedTreatmentGlioblastoma Multiforme (GBM)1
1CompletedTreatmentSquamous Cell Tumors1
1, 2Active Not RecruitingTreatmentGlioblastoma Multiforme (GBM) / Glioblastomas / Malignant Gliomas1
2Active Not RecruitingTreatmentGlioblastoma Multiforme (GBM)1
2TerminatedTreatmentFollicular Lymphoma, Grade 3b / Lymphoma, B-Cell / Lymphoma, Follicular, Grade 3b / Lymphoma, Large B-Cell, Diffuse (DLBCL)1
2TerminatedTreatmentFollicular Lymphoma, Grade 3b / Lymphoma, Large B-Cell, Diffuse (DLBCL) / Transformed Lymphoma / DLBCL1
2, 3Active Not RecruitingTreatmentGlioblastoma Multiforme (GBM) / Glioblastomas / Gliosarcoma1
3Active Not RecruitingTreatmentCancer - Glioblastoma / Glioblastoma Multiforme (GBM)1
Not AvailableNo Longer AvailableNot AvailableGlioblastoma or Solid Tumors, Epidermal Growth Factor Receptor (EGFR) Diagnosis / Malignancies1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00598 mg/mLALOGPS
logP4.34ALOGPS
logP5.66ChemAxon
logS-5.2ALOGPS
pKa (Strongest Acidic)3.89ChemAxon
pKa (Strongest Basic)1.6ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count13ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area219.25 Å2ChemAxon
Rotatable Bond Count27ChemAxon
Refractivity249.46 m3·mol-1ChemAxon
Polarizability98.49 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as hybrid peptides. These are compounds containing at least two different types of amino acids (alpha, beta, gamma, delta) linked to each other through a peptide bond.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Peptidomimetics
Sub Class
Hybrid peptides
Direct Parent
Hybrid peptides
Alternative Parents
Dipeptides / Phenylalanine and derivatives / Valine and derivatives / N-acyl-L-alpha-amino acids / Alpha amino acid amides / Phenylpropanoic acids / Amphetamines and derivatives / N-acylpyrrolidines / Maleimides / N-substituted carboxylic acid imides
show 14 more
Substituents
Hybrid peptide / Alpha-dipeptide / Phenylalanine or derivatives / N-acyl-alpha-amino acid / Valine or derivatives / N-acyl-alpha amino acid or derivatives / N-acyl-l-alpha-amino acid / Alpha-amino acid amide / 3-phenylpropanoic-acid / Alpha-amino acid or derivatives
show 32 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Antibody
General Function
Ubiquitin protein ligase binding
Specific Function
Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TG...
Gene Name
EGFR
Uniprot ID
P00533
Uniprot Name
Epidermal growth factor receptor
Molecular Weight
134276.185 Da
References
  1. Phillips AC, Boghaert ER, Vaidya KS, Mitten MJ, Norvell S, Falls HD, DeVries PJ, Cheng D, Meulbroek JA, Buchanan FG, McKay LM, Goodwin NC, Reilly EB: ABT-414, an Antibody-Drug Conjugate Targeting a Tumor-Selective EGFR Epitope. Mol Cancer Ther. 2016 Apr;15(4):661-9. doi: 10.1158/1535-7163.MCT-15-0901. Epub 2016 Feb 4. [PubMed:26846818]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Nucleotide exchange blocker
General Function
Ubiquitin protein ligase binding
Specific Function
Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain.
Gene Name
TUBB
Uniprot ID
P07437
Uniprot Name
Tubulin beta chain
Molecular Weight
49670.515 Da
References
  1. Bai RL, Pettit GR, Hamel E: Binding of dolastatin 10 to tubulin at a distinct site for peptide antimitotic agents near the exchangeable nucleotide and vinca alkaloid sites. J Biol Chem. 1990 Oct 5;265(28):17141-9. [PubMed:2211617]
  2. Waight AB, Bargsten K, Doronina S, Steinmetz MO, Sussman D, Prota AE: Structural Basis of Microtubule Destabilization by Potent Auristatin Anti-Mitotics. PLoS One. 2016 Aug 12;11(8):e0160890. doi: 10.1371/journal.pone.0160890. eCollection 2016. [PubMed:27518442]

Drug created on October 20, 2016 14:43 / Updated on June 04, 2019 07:26