Pralatrexate | CAS#146464-95-1 | DHFR inhibitor

MedKoo Cat#: 206221 | Name: Pralatrexate

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Pralatrexate is a folate analogue inhibitor of dihydrofolate reductase (DHFR) exhibiting high affinity for reduced folate carrier-1 (RFC-1) with antineoplastic and immunosuppressive activities. Pralatrexate selectively enters cells expressing RFC-1; intracellularly, this agent is highly polyglutamylated and competes for the folate binding site of DHFR, blocking tetrahydrofolate synthesis, which may result in depletion of nucleotide precursors; inhibition of DNA, RNA and protein synthesis; and apoptotic tumor cell death.

Chemical Structure

Pralatrexate

CAS#146464-95-1 (racemic)

Theoretical Analysis

MedKoo Cat#: 206221

Name: Pralatrexate

CAS#: 146464-95-1 (racemic)

Chemical Formula: C23H23N7O5

Exact Mass: 477.1761

Molecular Weight: 477.47

Elemental Analysis: C, 57.86; H, 4.86; N, 20.53; O, 16.75

Price and Availability

Size	Price	Availability
5mg	USD 90.00	Ready to ship
10mg	USD 150.00	Ready to ship
25mg	USD 320.00	Ready to ship
50mg	USD 550.00	Ready to ship
100mg	USD 950.00	Ready to ship
200mg	USD 1,650.00	Ready to ship

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Related CAS #

1320211-69-5 (S-isomer) 1320211-70-8 (R-isomer) 146464-95-1 (racemic)

Synonym

Pralatrexate; 10-Propargyl-10-deazaaminopterin; PDX; brand name: Folotyn.

IUPAC/Chemical Name

N -(4-{1-[(2,4-diaminopteridin-6-yl)methyl]but-3-yn-1-yl}benzoyl)-L-glutamic acid

InChi Key

OGSBUKJUDHAQEA-WMCAAGNKSA-N

InChi Code

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

SMILES Code

O=C(O)CC[C@@H](C(O)=O)NC(C1=CC=C(C(CC2=NC3=C(N)N=C(N)N=C3N=C2)CC#C)C=C1)=O

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#T8Z10C31

QC Data

View QC data: current batch, Lot#T8Z10C31

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Pralatrexate is an antifolate and a dihydrofolate reductasean (DHFR) inhibitor with a Ki of 13.4 pM.

In vitro activity:

As shown in Figure 3A, MM.1s (multiple myeloma) cells treated with prlatrexate exhibited a distinct pattern of cell cycle events compared to untreated cells as early as 12 hours after exposure to the drug. Pralatrexate treated MM.1s cells accumulated in early G1/S phase transition, as demonstrated through 7-AAD and Bromodeoxyuridine (BrdU) co-staining (Figure 3A). Drug-treated MM.1s cells were able to initiate DNA synthesis, visualized as an increase in incorporation of pulsed BrdU (S-phase). However, the cells were unable to progress through S-phase, as visualized as by an increase in BrdU+ diploid (2n) cells. This effect was time and concentration dependent (Figure 3B). The cell cycle analysis of resistant U266 cells was unaltered following treatment with pralatrexate. Across all sensitive cell lines, pralatrexate induced cell cycle arrest in a concentration dependent manner. Reference: Oncotarget. 2020 May 5;11(18):1576-1589. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210016/

In vivo activity:

The in vivo efficacy of pralatrexate combined with bortezomib was investigated in a xenograft model of cutaneous T-cell lympoma (CTCL). After 30 days from the beginning of the experiment, the results in the combination group treated with pralatrexate at a dose of 15 mg/kg (1/4 of the maximum tolerated dose) and bortezomib given on days 1, 4, 8, and 11 at a dose of 0.5 mg/kg were statistically significant compared with pralatrexate alone (P = 0.002), bortezomib alone (P = 0.001), and the control (P = 0.001; Supplementary Data C). Interestingly, complete responses (CRs) were observed only in the combination cohort, where 6 of 10 mice experienced CR in the combination cohort at day 18, with two of those CRs being maintained beyond day 30. Neither significant weight loss nor death was observed in any of the cohorts. These data support the in vitro experiments in establishing the superior efficacy of this combination in T-cell malignancies. Reference: Clin Cancer Res. 2010 Jul 15;16(14):3648-58. https://clincancerres.aacrjournals.org/content/16/14/3648.long

	Solvent	mg/mL	mM
Solubility
	DMSO	3.0	6.30

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 477.47 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Kinahan C, Mangone MA, Scotto L, Visentin M, Marchi E, Cho HJ, O'Connor OA. The anti-tumor activity of pralatrexate (PDX) correlates with the expression of RFC and DHFR mRNA in preclinical models of multiple myeloma. Oncotarget. 2020 May 5;11(18):1576-1589. doi: 10.18632/oncotarget.27516. PMID: 32405334; PMCID: PMC7210016. 2. Marchi E, Paoluzzi L, Scotto L, Seshan VE, Zain JM, Zinzani PL, O'Connor OA. Pralatrexate is synergistic with the proteasome inhibitor bortezomib in in vitro and in vivo models of T-cell lymphoid malignancies. Clin Cancer Res. 2010 Jul 15;16(14):3648-58. doi: 10.1158/1078-0432.CCR-10-0671. Epub 2010 May 25. PMID: 20501616.

In vitro protocol:

In vivo protocol:

1. Marchi E, Paoluzzi L, Scotto L, Seshan VE, Zain JM, Zinzani PL, O'Connor OA. Pralatrexate is synergistic with the proteasome inhibitor bortezomib in in vitro and in vivo models of T-cell lymphoid malignancies. Clin Cancer Res. 2010 Jul 15;16(14):3648-58. doi: 10.1158/1078-0432.CCR-10-0671. Epub 2010 May 25. PMID: 20501616.

1: Spriano F, Tarantelli C, Cascione L, Gaudio E, Golino G, Scalise L, Cacciapuoti MT, Zucca E, Stathis A, Van Berkel PH, Inghirami G, Zammarchi F, Bertoni F. Targeting CD25+ lymphoma cells with the antibody-drug conjugate camidanlumab tesirine as a single agent or in combination with targeted agents. Br J Haematol. 2024 Jul 30. doi: 10.1111/bjh.19658. Epub ahead of print. PMID: 39080847. 2: Cliff ERS, Russler-Germain DA, Daval CJR, Kesselheim AS. US Food and Drug Administration's Directive to Deal With Delayed Confirmatory Trials: Lessons From Pralatrexate and Belinostat for T-Cell Lymphoma. J Clin Oncol. 2024 Jul 25:JCO2400100. doi: 10.1200/JCO.24.00100. Epub ahead of print. PMID: 39052948. 3: O'Connor OA, Ma H, Chan JYS, Kim SJ, Yoon SE, Kim WS. Peripheral T-cell lymphoma: From biology to practice to the future. Cancer Treat Rev. 2024 Sep;129:102793. doi: 10.1016/j.ctrv.2024.102793. Epub 2024 Jun 27. PMID: 39002211. 4: Ryu Tiger YK, Jain S, Barta SK, Tolu S, Estrella B, Sawas A, Lue JK, Francescone MM, Pro B, Amengual JE. Phase II study of the novel antifolate agent pralatrexate in combination with the histone deacetylase inhibitor romidepsin for the treatment of patients with mature T-cell lymphoma. Leuk Lymphoma. 2024 Jun;65(6):736-745. doi: 10.1080/10428194.2024.2329996. Epub 2024 Mar 22. PMID: 38517235; PMCID: PMC11162072. 5: O'Connor OA, Ko BS, Wang MC, Maruyama D, Song Y, Yeoh EM, Manamley N, Tobinai K. Pooled analysis of pralatrexate single-agent studies in patients with relapsed/refractory peripheral T-cell lymphoma. Blood Adv. 2024 Jun 11;8(11):2601-2611. doi: 10.1182/bloodadvances.2023010441. PMID: 38429077; PMCID: PMC11157204. 6: Wu J, Cai Y, Jiang N, Qian Y, Lyu R, You Q, Zhang F, Tao H, Zhu H, Nawaz W, Chen D, Wu Z. Pralatrexate inhibited the replication of varicella zoster virus and vesicular stomatitis virus: An old dog with new tricks. Antiviral Res. 2024 Jan;221:105787. doi: 10.1016/j.antiviral.2023.105787. Epub 2023 Dec 23. PMID: 38145756. 7: Iyer SP, Johnston PB, Barta SK. Pralatrexate injection combined with CHOP for treatment of PTCL: results from the Fol-CHOP dose-finding phase 1 trial. Blood Adv. 2024 Jan 23;8(2):353-364. doi: 10.1182/bloodadvances.2023011095. PMID: 38029357; PMCID: PMC10788850. 8: Chen NC, Chang H, Kuo MC, Lin TL, Shih LY, Chuang WY, Kao HW. Predictive model for treatment outcomes of peripheral T-cell lymphoma, not otherwise specified, in Taiwanese patients. J Formos Med Assoc. 2024 Feb;123(2):188-197. doi: 10.1016/j.jfma.2023.07.014. Epub 2023 Aug 7. PMID: 37558588. 9: Mandal SK, Puri S, Kumar BK, Muzaffar-Ur-Rehman M, Sharma PK, Sankaranarayanan M, Deepa PR. Targeting lipid-sensing nuclear receptors PPAR (α, γ, β/δ): HTVS and molecular docking/dynamics analysis of pharmacological ligands as potential pan-PPAR agonists. Mol Divers. 2024 Jun;28(3):1423-1438. doi: 10.1007/s11030-023-10666-y. Epub 2023 Jun 6. PMID: 37280404. 10: Hamp A, Hanson J, Schwartz RA, Lambert WC, Alhatem A. Dupilumab-associated mycosis fungoides: a cross-sectional study. Arch Dermatol Res. 2023 Nov;315(9):2561-2569. doi: 10.1007/s00403-023-02652-z. Epub 2023 Jun 4. PMID: 37270763. 11: Iaconis D, Caccuri F, Manelfi C, Talarico C, Bugatti A, Filippini F, Zani A, Novelli R, Kuzikov M, Ellinger B, Gribbon P, Riecken K, Esposito F, Corona A, Tramontano E, Beccari AR, Caruso A, Allegretti M. DHFR Inhibitors Display a Pleiotropic Anti-Viral Activity against SARS-CoV-2: Insights into the Mechanisms of Action. Viruses. 2023 May 9;15(5):1128. doi: 10.3390/v15051128. PMID: 37243214; PMCID: PMC10221469. 12: Prajapat M, Sarma P, Shekhar N, Chauhan A, Kaur G, Bhattacharyya A, Avti P, Choudhary G, Bansal S, Sharma S, Kaur H, Kumar S, Mann H, Raja A, Singh A, Singh R, Sharma AR, Prakash A, Medhi B. Virtual screening and molecular dynamics simulation study of approved drugs as a binder to the linoleic acid binding site on spike protein of SARS-CoV-2 and double mutant (E484Q and L452R). Indian J Pharmacol. 2022 Nov-Dec;54(6):431-442. doi: 10.4103/ijp.ijp_111_22. PMID: 36722555; PMCID: PMC10043821. 13: Kari S, Murugesan A, Thiyagarajan R, Kidambi S, Razzokov J, Selvaraj C, Kandhavelu M, Marimuthu P. Bias-force guided simulations combined with experimental validations towards GPR17 modulators identification. Biomed Pharmacother. 2023 Apr;160:114320. doi: 10.1016/j.biopha.2023.114320. Epub 2023 Jan 28. PMID: 36716660. 14: Truong K, Bhattacharyya A, Smee R, Kim J, Wells J. Pralatrexate and total skin electron beam therapy as bridging agents to allogeneic stem cell transplantation in severely treatment-refractory Sezary syndrome. Int J Dermatol. 2023 Apr;62(4):e219-e221. doi: 10.1111/ijd.16587. Epub 2023 Jan 22. PMID: 36683181. 15: Ghasemi L, Jahani S, Ghazizadeh M, Foroughi MM. A novel and ultrasensitive electrochemical DNA biosensor for pralatrexate detection. Anal Methods. 2023 Feb 2;15(5):631-638. doi: 10.1039/d2ay01909d. PMID: 36651313. 16: Weng W, Hong J, Owusu-Ansah KG, Chen B, Zheng S, Jiang D. Pralatrexate mediates effective killing of gemcitabine-resistant pancreatic cancer: role of mTOR/4E-BP1 signal pathway. Heliyon. 2022 Dec 6;8(12):e12064. doi: 10.1016/j.heliyon.2022.e12064. PMID: 36544829; PMCID: PMC9761725. 17: Kovalev IS, Zyryanov GV, Santra S, Majee A, Varaksin MV, Charushin VN. Folic Acid Antimetabolites (Antifolates): A Brief Review on Synthetic Strategies and Application Opportunities. Molecules. 2022 Sep 22;27(19):6229. doi: 10.3390/molecules27196229. PMID: 36234766; PMCID: PMC9573478. 18: Wang Y, Wang H, Wang X. Palbociclib regulates the expression of dihydrofolate reductase and the cell cycle to inhibit t (11;14) multiple myeloma. Ann Transl Med. 2022 Jul;10(13):746. doi: 10.21037/atm-22-2830. PMID: 35957711; PMCID: PMC9358508. 19: Zhang H, Gong X, Peng Y, Saravanan KM, Bian H, Zhang JZH, Wei Y, Pan Y, Yang Y. An Efficient Modern Strategy to Screen Drug Candidates Targeting RdRp of SARS-CoV-2 With Potentially High Selectivity and Specificity. Front Chem. 2022 Jul 12;10:933102. doi: 10.3389/fchem.2022.933102. PMID: 35903186; PMCID: PMC9315156. 20: Altınay S, Kural A, Özmen A, Tural D, Tutar Y. Pralatrexate for Peripheral T-Cell Lymphoma (PTCL): Chance Only Supports The Prepared Mind. Anticancer Agents Med Chem. 2023;23(3):298-305. doi: 10.2174/1871520622666220610151603. PMID: 35692151.