Thymidylate synthase inhibitor

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Thymidylate synthase inhibitors are chemical agents which inhibit the enzyme thymidylate synthase and have potential as an anticancer chemotherapy. [1] This inhibition prevents the methylation of C5 of deoxyuridine monophosphate (dUMP) thereby inhibiting the synthesis of deoxythymidine monophosphate (dTMP). The downstream effect is promotion of cell death because cells would not be able to properly undergo DNA synthesis if they are lacking dTMP, a necessary precursor to dTTP. [2] Five agents were in clinical trials in 2002: raltitrexed, pemetrexed, nolatrexed, ZD9331, and GS7904L. [3]

Examples include

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HAT medium

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Raltitrexed

{{Drugbox | verifiedrevid = 464379925 | IUPAC_name = N-[(5-{methyl[ methyl]amino}-2-thienyl)carbonyl]-L-glutamic acid | image = Raltitrexed.svg | image2 = Raltitrexed ball-and-stick.png | tradename = | Drugs.com = Micromedex Detailed Consumer Information | pregnancy_AU = | pregnancy_US = | pregnancy_category = | legal_AU = | legal_UK = POM | legal_US = Not available | legal_status = | routes_of_administration = Intravenous | bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion = | IUPHAR_ligand = 7403 | CAS_number_Ref =   | CAS_number = 112887-68-0 | ATC_prefix = L01 | ATC_suffix = BA03 | ATC_supplemental = | PubChem = 104758 | DrugBank_Ref =   | DrugBank = DB00293 | ChemSpiderID_Ref =   | ChemSpiderID = 94568 | UNII_Ref =   | UNII = FCB9EGG971 | KEGG_Ref =   | KEGG = D01064 | ChEMBL_Ref =   | ChEMBL = 225071 | PDB_ligand = D16 | C=21 | H=22 | N=4 | O=6 | S=1 | smiles = O=C(c3sc cc3)N[C@H](C O)CCC(=O)O | StdInChI_Ref =   | StdInChI = 1S/C21H22N4O6S/c1-11-22-14-4-3-12(9-13 19 23-11)10-25(2)17-7-6-16(32-17)20(29)24-15(21 31)5-8-18(26)27/h3-4,6-7,9,15H,5,8,10H2,1-2H3,(H,24,29)(H,26,27)(H,30,31)(H,22,23,28)/t15-/m0/s1 | StdInChIKey_Ref =   | StdInChIKey = IVTVGDXNLFLDRM-HNNXBMFYSA-N }}

Thymidylate synthase

Thymidylate synthase (TS) is an enzyme that catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Thymidine is one of the nucleotides in DNA. With inhibition of TS, an imbalance of deoxynucleotides and increased levels of dUMP arise. Both cause DNA damage.

5,10-Methylenetetrahydrofolate Chemical compound

5,10-Methylenetetrahydrofolate (N5,N10-Methylenetetrahydrofolate; 5,10-CH2-THF) is cofactor in several biochemical reactions. It exists in nature as the diastereoisomer [6R]-5,10-methylene-THF.

Thymidylate synthase (FAD)

In enzymology, a thymidylate synthase (FAD) (EC 2.1.1.148) is an enzyme that catalyzes the chemical reaction

Antifolate Class of antimetabolite medications

Antifolates are a class of antimetabolite medications that antagonise (that is, block) the actions of folic acid (vitamin B9). Folic acid's primary function in the body is as a cofactor to various methyltransferases involved in serine, methionine, thymidine and purine biosynthesis. Consequently, antifolates inhibit cell division, DNA/RNA synthesis and repair and protein synthesis. Some such as proguanil, pyrimethamine and trimethoprim selectively inhibit folate's actions in microbial organisms such as bacteria, protozoa and fungi. The majority of antifolates work by inhibiting dihydrofolate reductase (DHFR).

Carmofur

Carmofur (INN) or HCFU (1-hexylcarbamoyl-5-fluorouracil) is a pyrimidine analogue used as an antineoplastic agent. It is a derivative of fluorouracil, being a lypophilic-masked analog of 5-FU that can be administered orally.

OSI-7904

OSI-7904 is a noncompetitive liposomal thymidylate synthase inhibitor. OSI-7904 is a benzoquinazoline folate analog with antineoplastic activity. As a thymidylate synthase inhibitor, OSI-7904 noncompetitively binds to thymidylate synthase, resulting in inhibition of thymine nucleotide synthesis and DNA replication.

Thymectacin

Thymectacin is an anticancer prodrug of brivudine monophosphate. It developed by New Biotics and it has entered in phase I clinical trials for colon cancer.

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Thymidylate kinase

Thymidylate kinase catalyzes the phosphorylation of thymidine 5'-monophosphate (dTMP) to form thymidine 5'-diphosphate (dTDP) in the presence of ATP and magnesium:

Trifluridine/tipiracil

Trifluridine/tipiracil, sold under the brand name Lonsurf, is a fixed-dose combination medication that is used as a third- or fourth-line treatment of metastatic colorectal cancer or gastric cancer, after chemotherapy and targeted therapeutics have failed. It is a combination of two active pharmaceutical ingredients: trifluridine, a nucleoside analog, and tipiracil, a thymidine phosphorylase inhibitor. Tipiracil prevents rapid metabolism of trifluridine, increasing the bioavailability of trifluridine.

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ONX-0801

ONX-0801 is an experimental drug that has been developed to target ovarian cancer. It is a folate receptor alpha mediated thymidylate synthase inhibitor.

Professor Kenneth Reginald Harrap (1931-2017) was a British oncological biochemist.

Fluorodeoxyuridylate Chemical compound

Fluorodeoxyuridylate, also known as FdUMP, 5-Fluoro-2'-deoxyuridylate, or 5-Fluoro-2'-deoxyuridine 5'-monophosphate sodium salt, is a molecule formed in vivo from 5-fluorouracil or 5-fluorodeoxyuridin.

References

  1. Jackman AL, Calvert AH (November 1995). "Folate-based thymidylate synthase inhibitors as anticancer drugs". Annals of Oncology. 6 (9): 871–81. doi: 10.1093/oxfordjournals.annonc.a059353 . PMID   8624289.
  2. Ackland SP, Clarke SJ, Beale P, Peters GJ (December 2006). "Thymidylate synthase inhibitors". Update on Cancer Therapeutics. 1 (4): 403–427. doi:10.1016/j.uct.2006.09.001.
  3. "Thymidylate synthase inhibitors as anticancer agents: from bench to bedside" . Retrieved 2009-01-28.
  4. Liu Y, Wu W, Hong W, Sun X, Wu J, Huang Q (April 2014). "Raltitrexed-based chemotherapy for advanced colorectal cancer". Clinics and Research in Hepatology and Gastroenterology. 38 (2): 219–25. doi:10.1016/j.clinre.2013.11.006. PMID   24388340.
  5. Papamichael D (1999). "The use of thymidylate synthase inhibitors in the treatment of advanced colorectal cancer: current status". The Oncologist. 4 (6): 478–87. doi:10.1634/theoncologist.4-6-478. PMID   10631692.
  6. Gibbs DD, Theti DS, Wood N, Green M, Raynaud F, Valenti M, Forster MD, Mitchell F, Bavetsias V, Henderson E, Jackman AL (December 2005). "BGC 945, a novel tumor-selective thymidylate synthase inhibitor targeted to alpha-folate receptor-overexpressing tumors". Cancer Research. 65 (24): 11721–8. doi: 10.1158/0008-5472.CAN-05-2034 . PMID   16357184.
  7. Ricart AD, Berlin JD, Papadopoulos KP, Syed S, Drolet DW, Quaratino-Baker C, Horan J, Chick J, Vermeulen W, Tolcher AW, Rowinsky EK, Rothenberg ML (December 2008). "Phase I, pharmacokinetic and biological correlative study of OSI-7904L, a novel liposomal thymidylate synthase inhibitor, and cisplatin in patients with solid tumors". Clinical Cancer Research. 14 (23): 7947–55. doi: 10.1158/1078-0432.CCR-08-0864 . PMID   19047127.