Pralatrexate

Targets (2)Enzymes (1)Transporters (1)Biointeractions (4)

Identification

Name
Pralatrexate
Accession Number
DB06813  (DB05527)
Type
Small Molecule
Groups
Approved, Investigational
Description

Pralatrexate is an antimetabolite for the treatment of relapsed or refractory peripheral T-cell lymphoma. It is more efficiently retained in cancer cells than methotrexate. FDA approved on September 24, 2009.

Structure
Thumb
3D
Similar Structures
Synonyms
  • (2S)-2-((4-((1RS)-1-((2,4-diaminopteridin-6-yl)methyl)but-3-ynyl)benzoyl)amino)pentanedioic acid
  • (2S)-2-({4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]benzoyl}amino)pentanedioic acid
  • 10-Propargyl-10-deazaaminopterin
  • N-(4-(1-((2,4-Diamino-6-pteridinyl)methyl)-3-butynyl)benzoyl)-L-glutamic acid
  • PDX
  • Pralatrexato
  • Pralatrexatum
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
FolotynInjection20 mg/1mLIntravenousAllos Therapeutics2009-09-24Not applicableUs
Categories
UNII
A8Q8I19Q20
CAS number
146464-95-1
Weight
Average: 477.4726
Monoisotopic: 477.176066881
Chemical Formula
C23H23N7O5
InChI Key
OGSBUKJUDHAQEA-WMCAAGNKSA-N
InChI
InChI=1S/C23H23N7O5/c1-2-3-14(10-15-11-26-20-18(27-15)19(24)29-23(25)30-20)12-4-6-13(7-5-12)21(33)28-16(22(34)35)8-9-17(31)32/h1,4-7,11,14,16H,3,8-10H2,(H,28,33)(H,31,32)(H,34,35)(H4,24,25,26,29,30)/t14?,16-/m0/s1
IUPAC Name
(2S)-2-({4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]phenyl}formamido)pentanedioic acid
SMILES
NC1=NC2=NC=C(CC(CC#C)C3=CC=C(C=C3)C(=O)N[C@@H](CCC(O)=O)C(O)=O)N=C2C(N)=N1

Pharmacology

Indication

Treatment of relapsed or refractory peripheral T-cell lymphoma.

Associated Conditions
Pharmacodynamics

Pralatrexate is a 10-deazaaminopterin analogue of methotrexate. Compared to methotrexate, pralatrexate binds to RTC-1 with 10-times the affinity and is a more potent substrate for FPGS. As a result, pralatrexate is better internalized and retained in cancer cells and is more cytotoxic. Km, pralatrexate = 0.3 μmol/L; Km, methotrexate = 4.8 μmol/L; Vmax/Km (rate of intracellular transport), pralatrexate = 12.6 Vmax/Km (rate of intracellular transport), methotrexate = 0.9

Mechanism of action

The selectivity of pralatrexate for cancer cells is based upon the observation that cancer cells generally have an overexpression of reduced folate carrier protein-1 (RTC-1) compared to normal somatic cells. This carrier protein allows the entrance of pralatrexate into the cell. Upon entering the cell, folypolyglutamate synthase FPGS catalyzes the polyglutamination of pralatrexate so that it is retained inside the cell.
Once inside, pralatrexate competitively inhibits dihydrofolate reductase (DHFR) and thymidylate synthase. Subsequent depletion of thymidine monophosphate (TMP) occurs so that the cancer cell is unable to synthesize DNA and RNA. As a result, the cancer cell cannot proliferate and is forced to undergo apoptosis. Pralatrexate is more effective against cells that are actively dividing.

TargetActionsOrganism
ADihydrofolate reductase
inhibitor
Human
AThymidylate synthase
inhibitor
Human
Absorption

Pralatrexate demonstrates linear pharmacokinetics with a multiphasic decline with both diasteromers over dose range of 30-325 mg/m^2. Bioavailability, nonformulated preparation = 13 - 20%

Volume of distribution

Vss, R-pralatrexate = 37 L Vss, S-pralatrexate = 105 L

Protein binding

67 - 86% bound to plasma protein, albumin is the major binder. Does not significantly displace substrates from proteins.

Metabolism

No involvement of CYP450 enzyme system or glucuronidases.

Route of elimination

35% of drug is excreted unchanged in the urine (no difference between R- and S- pralatrexate). May be some net renal tubular excretion.

Half life

12-18 hours

Clearance

R- pralatrexate = 191 mL/min S- pralatrexate = 417 mL/min Mean clearance of both enantiomers is 220 mL/min.

Toxicity

Mucositis is the dose-limiting toxicity. Folic acid and vitamin B12 supplements do not prevent mucositis from happening.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(4R)-limoneneThe serum concentration of Pralatrexate can be increased when it is combined with (4R)-limonene.
AceclofenacThe serum concentration of Pralatrexate can be increased when it is combined with Aceclofenac.
AcemetacinThe serum concentration of Pralatrexate can be increased when it is combined with Acemetacin.
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Pralatrexate.
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Pralatrexate.
Acetylsalicylic acidThe serum concentration of Pralatrexate can be increased when it is combined with Acetylsalicylic acid.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Pralatrexate.
AlclofenacThe serum concentration of Pralatrexate can be increased when it is combined with Alclofenac.
AlclometasoneThe risk or severity of adverse effects can be increased when Pralatrexate is combined with Alclometasone.
AldesleukinThe risk or severity of adverse effects can be increased when Pralatrexate is combined with Aldesleukin.
Food Interactions
Not Available

References

General References
  1. Shimanovsky A, Dasanu CA: Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23. doi: 10.1517/14656566.2013.770474. Epub 2013 Feb 14. [PubMed:23409799]
  2. Gonen N, Assaraf YG: Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Updat. 2012 Aug;15(4):183-210. doi: 10.1016/j.drup.2012.07.002. Epub 2012 Aug 23. [PubMed:22921318]
  3. Rodd AL, Ververis K, Karagiannis TC: Safety and efficacy of pralatrexate in the management of relapsed or refractory peripheral T-cell lymphoma. Clin Med Insights Oncol. 2012;6:305-14. doi: 10.4137/CMO.S8536. Epub 2012 Aug 21. [PubMed:23032692]
External Links
KEGG Drug
D05589
PubChem Compound
148121
PubChem Substance
175427094
ChemSpider
130578
ChEBI
71223
ChEMBL
CHEMBL1201746
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Pralatrexate
ATC Codes
L01BA05 — Pralatrexate
FDA label
Download (266 KB)
MSDS
Download (479 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentAdvanced Cancers / Tumors, Solid1
1CompletedTreatmentCutaneous T-Cell Lymphoma (CTCL)1
1CompletedTreatmentCutaneous T-Cell Lymphoma (CTCL) / Mycosis Fungoides (MF) / Primary Cutaneous Anaplastic Large Cell Lymphoma / Sezary Syndrome1
1CompletedTreatmentMultiple Myeloma (MM)1
1CompletedTreatmentUnspecified Adult Solid Tumor, Protocol Specific2
1Not Yet RecruitingOtherCTCL / PTCL1
1RecruitingTreatmentPeripheral T-Cell Lymphoma (PTCL)1
1WithdrawnPreventionLung Cancer Non-Small Cell Cancer (NSCLC)1
1WithdrawnPreventionNon Hodgkin Lymphoma (NHL)1
1, 2CompletedTreatmentCancer of the Ovary / Fallopian Tube Cancer / Malignant Peritoneal Neoplasm1
1, 2CompletedTreatmentLymphoma, B-Cell / Lymphoma, Hodgkins / Peripheral T-Cell Lymphoma (PTCL) / Relapsed or Refractory Lymphoproliferative Malignancies / Waldenström's Macroglobulinemia (WM)1
1, 2CompletedTreatmentPeripheral T-Cell Lymphoma (PTCL)1
1, 2Not Yet RecruitingTreatmentRecurrent Mature T- and NK-Cell Non-Hodgkin Lymphoma / Recurrent Mycosis Fungoides / Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma / Refractory, advanced Mycosis fungoides1
1, 2RecruitingTreatmentLymphoid Malignancies / Lymphoma, Hodgkins / Malignant Lymphomas / Multiple Myeloma (MM) / Non-Hodgkin's Lymphoma (NHL)1
1, 2RecruitingTreatmentT-Cell Lymphomas1
2CompletedTreatmentAdenocarcinoma of the Esophagus / Adenocarcinomas of the Gastroesophageal Junction / Recurrent Esophageal Cancer / Squamous Cell Carcinoma of the Esophagus / Stage IV Esophageal Cancer1
2CompletedTreatmentAdenocarcinomas of the Gastroesophageal Junction / Advanced Gastric Cancer / Esophageal Undifferentiated Carcinoma / Gastric Adenocarcinoma / Gastric Squamous Cell Carcinoma / Recurrent Esophageal Adenocarcinoma / Recurrent Esophageal Squamous Cell Carcinoma / Recurrent Gastric Carcinoma / Stage IIIB Esophageal Adenocarcinoma / Stage IIIB Esophageal Squamous Cell Carcinoma / Stage IIIB Gastric Cancer / Stage IIIC Esophageal Adenocarcinoma / Stage IIIC Esophageal Squamous Cell Carcinoma / Stage IIIC Gastric Cancer / Stage IV Esophageal Adenocarcinoma / Stage IV Esophageal Squamous Cell Carcinoma / Undifferentiated Gastric Carcinoma1
2CompletedTreatmentAdult T-cell lymphomas/leukaemias1
2CompletedTreatmentAnaplastic Large Cell Lymphoma / Angioimmunoblastic T-Cell Lymphoma / Hepatosplenic T-Cell Lymphoma / Peripheral T-Cell Lymphoma (PTCL)1
2CompletedTreatmentBladder Cancers / Neoplasm, Bladder / Transitional Cell Carcinoma1
2CompletedTreatmentCancer of the Breast / Cancer, Breast / Human Mammary Carcinoma / Neoplasms, Breast / Tumors, Breast1
2CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
2CompletedTreatmentLung Cancers1
2CompletedTreatmentLymphoma, B-Cell1
2CompletedTreatmentMalignant Lymphomas1
2CompletedTreatmentPeripheral T-Cell Lymphoma (PTCL)1
2RecruitingPreventionRefractory Peripheral T-cell Lymphoma Unspecified / Relapsed Peripheral T-Cell Lymphoma1
3Active Not RecruitingTreatmentRecurrent Cutaneous T-cell lymphoma / Refractory Peripheral T-cell Lymphoma Unspecified1
3CompletedTreatmentRefractory Peripheral T-cell Lymphoma Unspecified / Relapsed Peripheral T-Cell Lymphoma1
3Not Yet RecruitingOtherLymphoma, T-Cell, Peripheral1
3TerminatedTreatmentPeripheral T-Cell Lymphoma (PTCL)1
4RecruitingTreatmentPeripheral T Cell Lymphoma (PTCL) / Progression, Disease1
Not AvailableCompletedNot AvailableRelapsed or Refractory Peripheral T-cell Lymphoma1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
InjectionIntravenous20 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6028071No2002-07-162022-07-16Us
US7622470No2005-05-312025-05-31Us
US8299078No2005-05-312025-05-31Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0178 mg/mLALOGPS
logP0.1ALOGPS
logP0.33ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)3.44ChemAxon
pKa (Strongest Basic)2.86ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count11ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area207.3 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity126.82 m3·mol-1ChemAxon
Polarizability47.31 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.6139
Blood Brain Barrier+0.5561
Caco-2 permeable-0.7518
P-glycoprotein substrateSubstrate0.5845
P-glycoprotein inhibitor INon-inhibitor0.9224
P-glycoprotein inhibitor IINon-inhibitor0.9921
Renal organic cation transporterNon-inhibitor0.938
CYP450 2C9 substrateNon-substrate0.8589
CYP450 2D6 substrateNon-substrate0.8269
CYP450 3A4 substrateNon-substrate0.6396
CYP450 1A2 substrateNon-inhibitor0.8654
CYP450 2C9 inhibitorNon-inhibitor0.8965
CYP450 2D6 inhibitorNon-inhibitor0.9073
CYP450 2C19 inhibitorNon-inhibitor0.9178
CYP450 3A4 inhibitorNon-inhibitor0.6523
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.934
Ames testNon AMES toxic0.8727
CarcinogenicityNon-carcinogens0.9543
BiodegradationNot ready biodegradable0.9493
Rat acute toxicity2.6263 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9803
hERG inhibition (predictor II)Non-inhibitor0.8735
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/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
MS/MS Spectrum - , positiveLC-MS/MSsplash10-004i-1513900000-5596beb52832aa3566cc

Taxonomy

Description
This compound belongs to the class of organic compounds known as glutamic acid and derivatives. These are compounds containing glutamic acid or a derivative thereof resulting from reaction of glutamic acid at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Glutamic acid and derivatives
Alternative Parents
N-acyl-alpha amino acids / Hippuric acids / Pteridines and derivatives / Aromatic monoterpenoids / Bicyclic monoterpenoids / Benzoyl derivatives / Aminopyrimidines and derivatives / Pyrazines / Imidolactams / Dicarboxylic acids and derivatives
show 11 more
Substituents
Glutamic acid or derivatives / Hippuric acid / N-acyl-alpha-amino acid / N-acyl-alpha amino acid or derivatives / Hippuric acid or derivatives / P-cymene / Aromatic monoterpenoid / Monoterpenoid / Bicyclic monoterpenoid / Pteridine
show 29 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
terminal acetylenic compound, N-acyl-L-glutamic acid, pteridines (CHEBI:71223)

Targets

Details1. Dihydrofolate reductase
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Nadph binding
Specific Function
Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA pre...
Gene Name
DHFR
Uniprot ID
P00374
Uniprot Name
Dihydrofolate reductase
Molecular Weight
21452.61 Da
References
  1. Shimanovsky A, Dasanu CA: Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23. doi: 10.1517/14656566.2013.770474. Epub 2013 Feb 14. [PubMed:23409799]
Details2. Thymidylate synthase
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Thymidylate synthase activity
Specific Function
Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.
Gene Name
TYMS
Uniprot ID
P04818
Uniprot Name
Thymidylate synthase
Molecular Weight
35715.65 Da
References
  1. Shimanovsky A, Dasanu CA: Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23. doi: 10.1517/14656566.2013.770474. Epub 2013 Feb 14. [PubMed:23409799]

Enzymes

Details1. Folylpolyglutamate synthase, mitochondrial
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Tetrahydrofolylpolyglutamate synthase activity
Specific Function
Catalyzes conversion of folates to polyglutamate derivatives allowing concentration of folate compounds in the cell and the intracellular retention of these cofactors, which are important substrate...
Gene Name
FPGS
Uniprot ID
Q05932
Uniprot Name
Folylpolyglutamate synthase, mitochondrial
Molecular Weight
64608.53 Da
References
  1. Shimanovsky A, Dasanu CA: Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23. doi: 10.1517/14656566.2013.770474. Epub 2013 Feb 14. [PubMed:23409799]

Transporters

Details1. Folate transporter 1
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Reduced folate carrier activity
Specific Function
Transporter for the intake of folate. Uptake of folate in human placental choriocarcinoma cells occurs by a novel mechanism called potocytosis which functionally couples three components, namely th...
Gene Name
SLC19A1
Uniprot ID
P41440
Uniprot Name
Folate transporter 1
Molecular Weight
64867.62 Da
References
  1. Gonen N, Assaraf YG: Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Updat. 2012 Aug;15(4):183-210. doi: 10.1016/j.drup.2012.07.002. Epub 2012 Aug 23. [PubMed:22921318]

Drug created on September 14, 2010 10:21 / Updated on August 02, 2018 05:40