General
Preferred name
PRALATREXATE
Synonyms
Folotyn ()
10-Propargyl-10-deazaaminopterin ()
Pralatrexate(Folotyn) ()
Pralatrexate (NSC 754230) ()
NSC 754230 ()
NSC-754230 ()
PDX ()
P&D ID
PD004103
CAS
146464-95-1
Tags
probe
natural product
drug
available
Approved by
PMDA
FDA
First approval
2009
Drug Status
investigational
approved
withdrawn
Drug indication
Peripheral T-cell lymphoma
Breast cancer
Max Phase
Phase 4
Probe info
Probe selectivity
protein-selective
Probe type
P&D approved
calculated probe
Probe sources
Probe targets
[[ compound.targets[t].gene_name ]]
Probe control
Probe control not defined
Orthogonal probes
2
No orthogonal probes found
Similar probes
0
No structurally similar probes found
Structure
P&D probe-likeness score
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
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%;
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
MOA
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.
DESCRIPTION
Inhibits dihydrofolate reductase, GAR transformylase and thymidylate synthase. The INN document specifies that pralatrexate is a racemic mixture of two epimers. These epimers are represented by the PubChem entries CID 23230419 and CID 11155808. We do not specify stereochemistry at the carbon atom which determines the two epimers, therefore our image represents the mixture.
SARS-CoV-2 and COVID-19: Pralatrexate has been identified as an inhibitor of the viral RNA-dependent RNA polymerase (RdRp; nsp12) from SARS-CoV-2 . This translates to inhibition of SARS-CoV-2 replication in vitro (EC50 8 nM). Structural anaylsis suggests that the interaction points between pralatrexate and RdRp are distinct from those between and RdRp. (GtoPdb)
SARS-CoV-2 and COVID-19: Pralatrexate has been identified as an inhibitor of the viral RNA-dependent RNA polymerase (RdRp; nsp12) from SARS-CoV-2 . This translates to inhibition of SARS-CoV-2 replication in vitro (EC50 8 nM). Structural anaylsis suggests that the interaction points between pralatrexate and RdRp are distinct from those between and RdRp. (GtoPdb)
[[ p.pathway_name ]]
[[ compound.targets[tid].gene_name ]]
Cell lines
2
Organisms
1
Compound Sets
22
AdooQ Bioactive Compound Library
Cayman Chemical Bioactives
ChEMBL Approved Drugs
ChEMBL Drugs
Concise Guide to Pharmacology 2017/18
DrugBank
DrugBank Approved Drugs
DrugCentral
DrugCentral Approved Drugs
DrugMAP
DrugMAP Approved Drugs
EU-OPENSCREEN Bioactive Compound Library
Guide to Pharmacology
MedChem Express Bioactive Compound Library
Natural product-based probes and drugs
NCATS Inxight Approved Drugs
NIH Approved Oncology Drugs
Probe Miner (suitable probes)
ReFrame library
Selleckchem Bioactive Compound Library
TargetMol Bioactive Compound Library
Withdrawn 2.0
[[ a.name ]]
[[ ligand_id ]]
free of charge
External IDs
31
Molecular Weight
477.18
Hydrogen Bond Acceptors
9
Hydrogen Bond Donors
5
Rotatable Bonds
10
Ring Count
3
Aromatic Ring Count
3
cLogP
0.98
TPSA
207.3
Fraction CSP3
0.26
Chiral centers
2.0
Largest ring
6.0
QED
0.26
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Pathway
Metabolism
Tyrosine Kinase/Adaptors
Cell Cycle/Checkpoint
DNA Damage/DNA Repair
Apoptosis
Cell Cycle/DNA Damage
Target
DHFR
Axl(KPL-4 cells )
Axl(SUM149 cells)
Antifolate
Apoptosis related,DHFR
ATC
L01BA05
Biosynthetic Origin
Other (Folate)
Therapeutic Indication
Anticancer
Source data
