Thymidylate synthase inhibitor

Last updated

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

Related Research Articles

A salvage pathway is a pathway in which nucleotides are synthesized from intermediates in the degradative pathway for nucleotides.

Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a medication used to treat cancer. By injection into a vein it is used for colon cancer, esophageal cancer, stomach cancer, pancreatic cancer, breast cancer, and cervical cancer. As a cream it is used for actinic keratosis, basal cell carcinoma, and skin warts.

Thymidine kinase InterPro Family

Thymidine kinase is an enzyme, a phosphotransferase : 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21. It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2. Certain viruses also have genetic information for expression of viral thymidine kinases. Thymidine kinase catalyzes the reaction:

Quinazoline is an organic compound with the formula C8H6N2. It is an aromatic heterocycle with a bicyclic structure consisting of two fused six-membered aromatic rings, a benzene ring and a pyrimidine ring. It is a light yellow crystalline solid that is soluble in water. Also known as 1,3-diazanaphthalene, quinazoline received its name from being an aza derivative of quinoline. Though the parent quinazoline molecule is rarely mentioned by itself in technical literature, substituted derivatives have been synthesized for medicinal purposes such as antimalarial and anticancer agents. Quinazoline is a planar molecule. It is isomeric with the other diazanaphthalenes of the benzodiazine subgroup: cinnoline, quinoxaline, and phthalazine.

HAT medium used in microbiology and immunology

HAT Medium is a selection medium for mammalian cell culture, which relies on the combination of aminopterin, a drug that acts as a powerful folate metabolism inhibitor by inhibiting dihydrofolate reductase, with hypoxanthine and thymidine which are intermediates in DNA synthesis. The trick is that aminopterin blocks DNA de novo synthesis, which is absolutely required for cell division to proceed, but hypoxanthine and thymidine provide cells with the raw material to evade the blockage, provided that they have the right enzymes, which means having functioning copies of the genes that encode them.

Betulinic acid chemical compound

Betulinic acid is a naturally occurring pentacyclic triterpenoid which has antiretroviral, antimalarial, and anti-inflammatory properties, as well as a more recently discovered potential as an anticancer agent, by inhibition of topoisomerase. It is found in the bark of several species of plants, principally the white birch from which it gets its name, but also the ber tree, selfheal, the tropical carnivorous plants Triphyophyllum peltatum and Ancistrocladus heyneanus, Diospyros leucomelas, a member of the persimmon family, Tetracera boiviniana, the jambul, flowering quince, rosemary, and Pulsatilla chinensis.

Raltitrexed chemical compound

{{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 | molecular_weight = 458.489 g/mol | 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 }}

Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases, which are enzymes that control the changes in DNA structure by catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle.

Thymidylate synthase mammalian protein found in Homo sapiens

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.

Levomefolic acid chemical compound

Levomefolic acid (INN) (also known as L-5-MTHF, L-methylfolate and L-5-methyltetrahydrofolate and (6S)-5-methyltetrahydrofolate, and (6S)-5-MTHF) is the primary biologically active form of folate used at the cellular level for DNA reproduction, the cysteine cycle and the regulation of homocysteine. It is also the form found in circulation and transported across membranes into tissues and across the blood-brain barrier. In the cell, L-methylfolate is used in the methylation of homocysteine to form methionine and tetrahydrofolate (THF). THF is the immediate acceptor of one carbon units for the synthesis of thymidine-DNA, purines (RNA and DNA) and methionine. The un-methylated form, folic acid (vitamin B9), is a synthetic form of folate, and must undergo enzymatic reduction by dihydrofolate reductase (DHFR) to become biologically active.

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.

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 chemical compound

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 chemical compound

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 chemical compound

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.

Thymidylate kinase class of enzymes

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 chemical compound

Trifluridine/tipiracil is a combination drug that is used as a third- or fourth-line treatment of metastatic colorectal 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.

Antineoplastic resistance, often used interchangeably with chemotherapy resistance, is the resistance of neoplastic (cancerous) cells, or the ability of cancer cells to survive and grow despite anti-cancer therapies. In some cases, cancers can evolve resistance to multiple drugs, called multiple drug resistance.

ONX-0801 chemical compound

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

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, A.L.; Calvert, A.H. (1995). "Folate-based thymidylate synthase inhibitors as anticancer drugs". Annals of Oncology. 6 (9): 871–881. doi: 10.1093/oxfordjournals.annonc.a059353 . PMID   8624289.
  2. Ackland, Stephen (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. Papamichael, D. (1999). "The use of thymidylate synthase inhibitors in the treatment of advanced colorectal cancer: current status". Oncologist. 4 (6): 478–87. PMID   10631692.
  5. Gibbs, David D.; et al. (2005). "BGC 945, a novel tumor-selective thymidylate synthase inhibitor targeted to α-folate receptor-overexpressing tumors". Cancer Research. 65 (24): 11721–11728. doi: 10.1158/0008-5472.CAN-05-2034 . PMID   16357184.
  6. Ricart AD, Berlin JD, Papadopoulos KP, et al. (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". Clin. Cancer Res. 14 (23): 7947–55. doi: 10.1158/1078-0432.CCR-08-0864 . PMID   19047127.