Nolatrexed HCl
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MedKoo CAT#: 206596

CAS#: 152946-68-4 (HCl salt)

Description: Nolatrexed, also known as AG337, is a thymidylate synthase inhibitor with potential anticancer activity. A phase II study of nolatrexed in 2007 in advanced HCC patients demonstrated minimal activity and significant stomatitis. Hence, it does not warrant further study as a single agent for this disease.

Chemical Structure

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Nolatrexed HCl
CAS# 152946-68-4 (HCl salt)
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 206596
Name: Nolatrexed HCl
CAS#: 152946-68-4 (HCl salt)
Chemical Formula: C14H14Cl2N4OS
Exact Mass: 356.03
Molecular Weight: 357.250
Elemental Analysis: C, 47.07; H, 3.95; Cl, 19.85; N, 15.68; O, 4.48; S, 8.97

Price and Availability

Size Price Availability Quantity
10mg USD 110 Ready to ship
25mg USD 225 Ready to ship
50mg USD 385 Ready to ship
100mg USD 650 Ready to ship
200mg USD 1050 Ready to ship
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Related CAS #: 152946-68-4 (HCl salt); 147149-76-6 (free base)  

Synonym: AG337; AG 337; AG-337; Nolatrexed HCl; Nolatrexed dihydrochloride; brand name: Thymitaq.

IUPAC/Chemical Name: 2-Amino-6-methyl-5-(4-pyridylthio)-1H-quinazolin-4-one dihydrochloride

InChi Key: PJKVJJYMWOCLIJ-UHFFFAOYSA-N

InChi Code: InChI=1S/C14H12N4OS.2ClH/c1-8-2-3-10-11(13(19)18-14(15)17-10)12(8)20-9-4-6-16-7-5-9;;/h2-7H,1H3,(H3,15,17,18,19);2*1H

SMILES Code: O=C1N=C(N)NC2=C1C(SC3=CC=NC=C3)=C(C)C=C2.[H]Cl.[H]Cl

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: Nolatrexed dihydrochloride (AG 337) is a non-competitive lipophilic inhibitor of thymidylate synthase.
In vitro activity: AG337 inhibits purified recombinant human TS (thymidylate synthase) with a Ki of 11 nM, and displays non-competitive inhibition kinetics. It was further shown to inhibit cell growth in a panel of cell lines of murine and human origin, displaying an IC50 of between 0.39 microM 6.6 microM. TS was suggested as the locus of action of AG337 by the ability of thymidine to antagonize cell growth inhibition and the direct demonstration of TS inhibition in whole cells using a tritium release assay. The demonstration, by flow cytometry, that AG337-treated L1210 cells were arrested in the S phase of the cell cycle was also consistent with a blockage of TS, as was the pattern of ribonucleotide and deoxyribonucleotide pool modulation in AG337-treated cells, which showed significant reduction in TTP levels. Reference: Cancer Chemother Pharmacol. 1996;37(6):509-17. https://link.springer.com/article/10.1007%2Fs002800050422
In vivo activity: In vivo, AG337 was highly active against the thymidine kinase-deficient murine L5178Y/TK-lymphoma implanted either i.p. or i.m. following i.p. or oral delivery. Prolonged dosing periods of 5 or 10 days were required for activity, and efficacy was improved with twice-daily dose administration. Dose levels of 25 mg/kg delivered i.p. twice daily for 10 days, 50 mg/kg once daily for 10 days, or 100 mg/kg once daily for 5 days elicited 100% cures against the i.p. tumor. Doses required for activity against the i.m. tumor were higher (100 mg/kg i.p. twice daily for 5 or 10 days) but demonstrated the ability of AG337 to penetrate solid tissue barriers. Oral delivery required doses of > or = 150 mg/kg twice daily for periods of 5-10 days to produce 100% cure rates against both i.m. and i.p. implanted tumors. Reference: Cancer Chemother Pharmacol. 1996;37(6):509-17. https://link.springer.com/article/10.1007%2Fs002800050422

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 15.0 42.00
H2O 2.0 5.60

Preparing Stock Solutions

The following data is based on the product molecular weight 357.25 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. Webber S, Bartlett CA, Boritzki TJ, Hillard JA, Howland EF, Johnston AL, Kosa M, Margosiak SA, Morse CA, Shetty BV. AG337, a novel lipophilic thymidylate synthase inhibitor: in vitro and in vivo preclinical studies. Cancer Chemother Pharmacol. 1996;37(6):509-17. doi: 10.1007/s002800050422. PMID: 8612303.
In vitro protocol: 1. Webber S, Bartlett CA, Boritzki TJ, Hillard JA, Howland EF, Johnston AL, Kosa M, Margosiak SA, Morse CA, Shetty BV. AG337, a novel lipophilic thymidylate synthase inhibitor: in vitro and in vivo preclinical studies. Cancer Chemother Pharmacol. 1996;37(6):509-17. doi: 10.1007/s002800050422. PMID: 8612303.
In vivo protocol: 1. Webber S, Bartlett CA, Boritzki TJ, Hillard JA, Howland EF, Johnston AL, Kosa M, Margosiak SA, Morse CA, Shetty BV. AG337, a novel lipophilic thymidylate synthase inhibitor: in vitro and in vivo preclinical studies. Cancer Chemother Pharmacol. 1996;37(6):509-17. doi: 10.1007/s002800050422. PMID: 8612303.

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1: Zheng J, Lin J, Wang L, Zhou J, Xie B, Xu T, Zhang W. Metastatic nasopharyngeal carcinoma outcomes in patients on cisplatin with nolatrexed or 5-fluorouracil. Oncol Res Treat. 2014;37(10):540-4. doi: 10.1159/000368107. Epub 2014 Sep 16. PubMed PMID: 25342504.

2: Tian SB, Jing CQ, Li LP. [Effects of RNA interference and nolatrexed on thymidylate synthase expression and cell proliferation of human colorectal carcinoma LOVO cells]. Zhonghua Wei Chang Wai Ke Za Zhi. 2012 Nov;15(11):1187-91. Chinese. PubMed PMID: 23172536.

3: Wang GF, Zhang JY, Wu SY, Xu W, Wan SH, Shao CF, Zhang JJ. [Measurement of plasma concentration and bioavailability of nolatrexed dihydrochloride in mice]. Nan Fang Yi Ke Da Xue Xue Bao. 2008 Nov;28(11):1993-5. Chinese. PubMed PMID: 19033111.

4: Chen SZ, Wang SM, Zhang JR. [Preparation of long-circulating nolatrexed dihydrochloride liposomes and its antitumor activity]. Nan Fang Yi Ke Da Xue Xue Bao. 2008 Mar;28(3):403-5. Chinese. PubMed PMID: 18359701.

5: Gish RG, Porta C, Lazar L, Ruff P, Feld R, Croitoru A, Feun L, Jeziorski K, Leighton J, Gallo J, Kennealey GT. Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin. J Clin Oncol. 2007 Jul 20;25(21):3069-75. PubMed PMID: 17634485.

6: Jhawer M, Rosen L, Dancey J, Hochster H, Hamburg S, Tempero M, Clendeninn N, Mani S. Phase II trial of nolatrexed dihydrochloride [Thymitaq, AG 337] in patients with advanced hepatocellular carcinoma. Invest New Drugs. 2007 Feb;25(1):85-94. Epub 2006 Sep 7. PubMed PMID: 16957834.

7: Li YL, Wu SG. [Effects of nolatrexed on thymidylate synthase protein expression]. Di Yi Jun Yi Da Xue Xue Bao. 2004 Aug;24(8):881-4. Chinese. PubMed PMID: 15321751.

8: Pivot X, Wadler S, Kelly C, Ruxer R, Tortochaux J, Stern J, Belpomme D, Humblet Y, Domenge C, Clendeninn N, Johnston A, Penning C, Schneider M. Result of two randomized trials comparing nolatrexed (Thymitaq) versus methotrexate in patients with recurrent head and neck cancer. Ann Oncol. 2001 Nov;12(11):1595-9. PubMed PMID: 11822760.

9: Estlin EJ, Pinkerton CR, Lewis IJ, Lashford L, McDowell H, Morland B, Kohler J, Newell DR, Boddy AV, Taylor GA, Price L, Ablett S, Hobson R, Pitsiladis M, Brampton M, Clendeninn N, Johnston A, Pearson AD. A phase I study of nolatrexed dihydrochloride in children with advanced cancer. A United Kingdom Children's Cancer Study Group Investigation. Br J Cancer. 2001 Jan 5;84(1):11-8. PubMed PMID: 11139306; PubMed Central PMCID: PMC2363615.

10: Hughes AN, Griffin MJ, Newell DR, Calvert AH, Johnston A, Kerr B, Lee C, Liang B, Boddy AV. Clinical pharmacokinetic and in vitro combination studies of nolatrexed dihydrochloride (AG337, Thymitaq) and paclitaxel. Br J Cancer. 2000 May;82(9):1519-27. PubMed PMID: 10789718; PubMed Central PMCID: PMC2363406.

11: Mok TS, Leung TW, Lee SD, Chao Y, Chan AT, Huang A, Lui MC, Yeo W, Chak K, Johnston A, Johnson P. A multi-centre randomized phase II study of nolatrexed versus doxorubicin in treatment of Chinese patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol. 1999;44(4):307-11. PubMed PMID: 10447578.

12: Stuart K, Tessitore J, Rudy J, Clendennin N, Johnston A. A Phase II trial of nolatrexed dihydrochloride in patients with advanced hepatocellular carcinoma. Cancer. 1999 Aug 1;86(3):410-4. PubMed PMID: 10430248.

13: Jodrell DI, Bowman A, Rye R, Byrne B, Boddy A, Rafi I, Taylor GA, Johnston A, Clendeninn NJ. A phase I study of the lipophilic thymidylate synthase inhibitor Thymitaq (nolatrexed dihydrochloride) given by 10-day oral administration. Br J Cancer. 1999 Feb;79(5-6):915-20. PubMed PMID: 10070890; PubMed Central PMCID: PMC2362691.

14: Hughes AN, Rafi I, Griffin MJ, Calvert AH, Newell DR, Calvete JA, Johnston A, Clendeninn N, Boddy AV. Phase I studies with the nonclassical antifolate nolatrexed dihydrochloride (AG337, THYMITAQ) administered orally for 5 days. Clin Cancer Res. 1999 Jan;5(1):111-8. PubMed PMID: 9918208.

15: Rafi I, Boddy AV, Calvete JA, Taylor GA, Newell DR, Bailey NP, Lind MJ, Green M, Hines J, Johnstone A, Clendeninn N, Calvert AH. Preclinical and phase I clinical studies with the nonclassical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors. J Clin Oncol. 1998 Mar;16(3):1131-41. PubMed PMID: 9508200.