Pralatrexate
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MedKoo CAT#: 206221

CAS#: 146464-95-1 (racemic)

Description: 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

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Pralatrexate
CAS# 146464-95-1 (racemic)

Theoretical Analysis

MedKoo Cat#: 206221
Name: Pralatrexate
CAS#: 146464-95-1 (racemic)
Chemical Formula: C23H23N7O5
Exact Mass: 477.18
Molecular Weight: 477.470
Elemental Analysis: C, 57.86; H, 4.86; N, 20.53; O, 16.75

Price and Availability

Size Price Availability Quantity
5mg USD 90 Ready to ship
10mg USD 150 Ready to ship
25mg USD 320 Ready to ship
50mg USD 550 Ready to ship
100mg USD 950 Ready to ship
200mg USD 1650 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:

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

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 3.0 6.30

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.

Recalculate based on batch purity %
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: 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.
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.

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1: Kelly KR, Gabrail N, Weitman S, Sarantopoulos J, Olszanski AJ, Edenfield W, Venitz J, Reddy G, Yang A, Hasal SJ, Lockhart AC. Phase 1 study evaluating the safety and pharmacokinetics of pralatrexate in relapsed/refractory advanced solid tumors and lymphoma patients with mild, moderate, and severe renal impairment. Cancer Chemother Pharmacol. 2016 Nov;78(5):929-939. PubMed PMID: 27638045.

2: Del Carmen MG, Supko JG, Horick NK, Rauh-Hain JA, Clark RM, Campos SM, Krasner CN, Atkinson T, Birrer MJ. Phase 1 and 2 study of carboplatin and pralatrexate in patients with recurrent, platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer. Cancer. 2016 Nov 15;122(21):3297-3306. doi: 10.1002/cncr.30196. PubMed PMID: 27421044.

3: Sastry RV, Venkatesan CS, Sastry BS, Mahesh K. Identification and characterization of forced degradation products of pralatrexate injection by LC-PDA and LC-MS. J Pharm Biomed Anal. 2016 Nov 30;131:400-409. doi: 10.1016/j.jpba.2016.08.023. PubMed PMID: 27643862.

4: Lee SS, Jung SH, Ahn JS, Kim YK, Cho MS, Jung SY, Lee JJ, Kim HJ, Yang DH. Pralatrexate in Combination with Bortezomib for Relapsed or Refractory Peripheral T Cell Lymphoma in 5 Elderly Patients. J Korean Med Sci. 2016 Jul;31(7):1160-3. doi: 10.3346/jkms.2016.31.7.1160. PubMed PMID: 27366017; PubMed Central PMCID: PMC4901011.

5: Dunn TJ, Dinner S, Price E, Coutré SE, Gotlib J, Hao Y, Berube C, Medeiros BC, Liedtke M. A phase 1, open-label, dose-escalation study of pralatrexate in combination with bortezomib in patients with relapsed/refractory multiple myeloma. Br J Haematol. 2016 Apr;173(2):253-9. doi: 10.1111/bjh.13946. PubMed PMID: 27040320.

6: McPherson JP, Vrontikis A, Sedillo C, Halwani AS, Gilreath JA. Pralatrexate Monitoring Using a Commercially Available Methotrexate Assay to Avoid Potential Drug Interactions. Pharmacotherapy. 2016 Feb;36(2):e8-e11. doi: 10.1002/phar.1699. PubMed PMID: 26809959.

7: Advani RH, Ansell SM, Lechowicz MJ, Beaven AW, Loberiza F, Carson KR, Evens AM, Foss F, Horwitz S, Pro B, Pinter-Brown LC, Smith SM, Shustov AR, Savage KJ, Vose JM. A phase II study of cyclophosphamide, etoposide, vincristine and prednisone (CEOP) Alternating with Pralatrexate (P) as front line therapy for patients with peripheral T-cell lymphoma (PTCL): final results from the T- cell consortium trial. Br J Haematol. 2016 Feb;172(4):535-44. doi: 10.1111/bjh.13855. PubMed PMID: 26627450.

8: Wood GS, Wu J. Methotrexate and Pralatrexate. Dermatol Clin. 2015 Oct;33(4):747-55. doi: 10.1016/j.det.2015.05.009. Review. PubMed PMID: 26433846.

9: Grem JL, Kos ME, Evande RE, Meza JL, Schwarz JK. A phase 1 clinical trial of sequential pralatrexate followed by a 48-hour infusion of 5-fluorouracil given every other week in adult patients with solid tumors. Cancer. 2015 Nov 1;121(21):3862-8. doi: 10.1002/cncr.29504. PubMed PMID: 26242208.

10: Petullo B, Wei L, Yereb M, Neal A, Rose J, Bekaii-Saab T, Wu C. A phase II study of biweekly pralatrexate and docetaxel in patients with advanced esophageal and gastroesophageal carcinoma that have failed first-line platinum-based therapy. J Gastrointest Oncol. 2015 Jun;6(3):336-40. doi: 10.3978/j.issn.2078-6891.2015.011. PubMed PMID: 26029462; PubMed Central PMCID: PMC4397239.

11: Tedeschi PM, Kathari YK, Johnson-Farley N, Bertino JR. Methylthioadenosine phosphorylase (MTAP)-deficient T-cell ALL xenografts are sensitive to pralatrexate and 6-thioguanine alone and in combination. Cancer Chemother Pharmacol. 2015 Jun;75(6):1247-52. doi: 10.1007/s00280-015-2747-2. PubMed PMID: 25917288; PubMed Central PMCID: PMC4441744.

12: Jain S, Jirau-Serrano X, Zullo KM, Scotto L, Palermo CF, Sastra SA, Olive KP, Cremers S, Thomas T, Wei Y, Zhang Y, Bhagat G, Amengual JE, Deng C, Karan C, Realubit R, Bates SE, O'Connor OA. Preclinical pharmacologic evaluation of pralatrexate and romidepsin confirms potent synergy of the combination in a murine model of human T-cell lymphoma. Clin Cancer Res. 2015 May 1;21(9):2096-106. doi: 10.1158/1078-0432.CCR-14-2249. PubMed PMID: 25677697.

13: Tedeschi PM, Kathari YK, Farooqi IN, Bertino JR. Leucovorin rescue allows effective high-dose pralatrexate treatment and an increase in therapeutic index in mesothelioma xenografts. Cancer Chemother Pharmacol. 2014 Nov;74(5):1029-32. doi: 10.1007/s00280-014-2580-z. PubMed PMID: 25205429; PubMed Central PMCID: PMC4209237.

14: A phase II study of cyclophosphamide, etoposide, vincristine and prednisone (CEOP) alternating with pralatrexate (P) as front line therapy for patients with peripheral T-cell lymphoma (PTCL): preliminary results from the T-Cell Consortium trial. Clin Adv Hematol Oncol. 2014 Feb;12(2 Suppl 5):6-7. PubMed PMID: 24852788.

15: Visentin M, Unal ES, Goldman ID. The impact of 5-formyltetrahydrofolate on the anti-tumor activity of pralatrexate, as compared to methotrexate, in HeLa cells in vitro. Cancer Chemother Pharmacol. 2014 May;73(5):1055-62. doi: 10.1007/s00280-014-2441-9. PubMed PMID: 24682532; PubMed Central PMCID: PMC4018754.

16: Dondi A, Bari A, Pozzi S, Ferri P, Sacchi S. The potential of pralatrexate as a treatment of peripheral T-cell lymphoma. Expert Opin Investig Drugs. 2014 May;23(5):711-8. doi: 10.1517/13543784.2014.902050. Review. PubMed PMID: 24661228.

17: Talpur R, Thompson A, Gangar P, Duvic M. Pralatrexate alone or in combination with bexarotene: long-term tolerability in relapsed/refractory mycosis fungoides. Clin Lymphoma Myeloma Leuk. 2014 Aug;14(4):297-304. doi: 10.1016/j.clml.2014.01.010. PubMed PMID: 24589156.

18: Ho AL, Lipson BL, Sherman EJ, Xiao H, Fury MG, Apollo A, Seetharamu N, Sima CS, Haque S, Lyo JK, Sales R, Cox L, Pfister DG. A phase II study of pralatrexate with vitamin B12 and folic acid supplementation for previously treated recurrent and/or metastatic head and neck squamous cell cancer. Invest New Drugs. 2014 Jun;32(3):549-54. doi: 10.1007/s10637-014-0073-x. PubMed PMID: 24566705.

19: Kerdel FA, Styperek AR, Maini A. Clinical remission of primary aggressive CD8+ cutaneous T-cell lymphoma after pralatrexate infusion. JAMA Dermatol. 2014 Mar;150(3):320-2. doi: 10.1001/jamadermatol.2013.8647. PubMed PMID: 24452280.

20: Marchi E, Mangone M, Zullo K, O'Connor OA. Pralatrexate pharmacology and clinical development. Clin Cancer Res. 2013 Dec 15;19(24):6657-61. doi: 10.1158/1078-0432.CCR-12-2251. PubMed PMID: 23965902.