Pralatrexate

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Cat Number

API0232140

CAS Number

146464-95-1

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CAS Number

146464-95-1

EINECS

680-662-0

Storage

Store at 2-8°C

Synonyms

Folotyn; 10-Propargyl-10-deazaaminopterin; pralatrexato; HSDB 7786; N-(4-(1-((2,4-Diamino-6-pteridinyl)methyl)-3-butynyl)benzoyl)-L-glutamic acid; pralatrexatum; DTXSID3048578; NSC-754230

Molecular Formula

C23H23N7O5

Molecular Weight

477.5

Smiles

C#CCC(CC1=CN=C2C(=N1)C(=NC(=N2)N)N)C3=CC=C(C=C3)C(=O)N[C@@H](CCC(=O)O)C(=O)O

Appearance

Light yellow to yellow powder

Melting Point

215°C (dec.)

Boiling Point

804.07°C

Relative Density

1.471±0.06 (Predicted)

General Description

Pralatrexate is a folate analogue antimetabolite that structurally resembles methotrexate but with a 10‑deazaaminopterin modification and an additional 3,4‑methylenedioxy substituent. This structural alteration increases its affinity for reduced folate carrier (RFC‑1) and for folylpolyglutamate synthetase (FPGS). The drug is a small‑molecule inhibitor of dihydrofolate reductase (DHFR).

Mechanism of Action

Pralatrexate is transported into cells via RFC‑1 and then polyglutamylated by FPGS, a process that traps the drug intracellularly and enhances its potency. The polyglutamated metabolite inhibits DHFR and other folate‑dependent enzymes, depleting thymidine and purine nucleotides. This leads to DNA synthesis disruption, cell cycle arrest in S‑phase, and apoptosis. Pralatrexate has much higher cellular uptake than methotrexate.

Application

Pralatrexate is indicated for the treatment of relapsed or refractory peripheral T‑cell lymphoma (PTCL), a rare and aggressive non‑Hodgkin lymphoma. It is also investigated in non‑small cell lung cancer and bladder cancer. Because of its high affinity for RFC‑1, it may overcome methotrexate resistance mechanisms associated with impaired transport or polyglutamylation.

Pralatrexate, a new‑generation DHFR inhibitor, has a 10‑fold higher affinity for the reduced folate carrier (RFC) than methotrexate (MTX), leading to greater intracellular accumulation and retention. After 6 hours in HeLa cells, 80% of intracellular pralatrexate was active polyglutamates (mainly tetraglutamate), whereas MTX polyglutamation was negligible. Pralatrexate’s affinity for the proton‑coupled folate transporter (PCFT) is lower than MTX, predicting less enterohepatic circulation and increased fecal excretion. Transient exposure growth inhibition was 375‑fold greater for pralatrexate than MTX. Enhanced activity is due to faster transport and polyglutamation.

Fig. 1 An analysis of pralatrexate accumulation and metabolism in HeLa cells. (Visentin M, et al., 2013)

References

Visentin M, et al. The membrane transport and polyglutamation of pralatrexate: a new-generation dihydrofolate reductase inhibitor. Cancer Chemother Pharmacol. 2013;72(3):597-606.

In vitro studies in Vero and human lung epithelial Calu‑3 cells showed that the anticancer drug pralatrexate reduced SARS‑CoV‑2 viral RNA copies in a dose‑dependent manner without detectable cytotoxicity. Treatment initiated up to 12 hours after infection still inhibited viral replication. These results suggest pralatrexate could be repurposed as a COVID‑19 antiviral, warranting further in vivo evaluation.

Fig. 2 Inhibitory effects of pralatrexate against influenza. (Bae JY, et al., 2021)

References

Bae JY, et al. Antiviral Efficacy of Pralatrexate against SARS-CoV-2. Biomol Ther (Seoul). 2021;29(3):268-272.

Does Pralatrexate require refrigerated storage as an antifolate analog?

Yes, it must be stored at 2-8°C. The compound is thermally labile; at room temperature, degradation via ring hydrolysis and oxidation occurs.

Is Pralatrexate sensitive to light, and how is this prevented?

Yes, it is photosensitive. Store in light-resistant containers and handle under subdued light to prevent photodegradation of the pteridine ring.

What is the stability of Pralatrexate after reconstitution for intravenous injection?

Reconstituted solutions are stable for up to 24 hours under refrigeration when protected from light.

How is the impurity 7-hydroxymethylpterin (a degradation product) monitored?

This degradation product is specifically quantified using a stability-indicating HPLC method, ensuring it remains within ICH limits.