Lometrexol

• CAT Number: R046382
• CAS Number: 106400-81-1
• Molecular Formula: C21H25N5O6
• Molecular Weight: 443.46
• Purity: ≥95%
• Storage: -20°C
• IUPAC Name: (2S)-2-[[4-[2-[(6R)-2-amino-4-oxo-5,6,7,8-tetrahydro-1H-pyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl]amino]pentanedioic acid
• InChI: InChI=1S/C21H25N5O6/c22-21-25-17-14(19(30)26-21)9-12(10-23-17)2-1-11-3-5-13(6-4-11)18(29)24-15(20(31)32)7-8-16(27)28/h3-6,12,15H,1-2,7-10H2,(H,24,29)(H,27,28)(H,31,32)(H4,22,23,25,26,30)/t12-,15+/m1/s1
• InChIKey: ZUQBAQVRAURMCL-DOMZBBRYSA-N
• SMILES: C1C(CNC2=C1C(=O)N=C(N2)N)CCC3=CC=C(C=C3)C(=O)NC(CCC(=O)O)C(=O)O

Lometrexol (CAS 106400-81-1) is a folate analog antimetabolite with antineoplastic activity. It inhibits  Glycinamide ribonucleotide formyltransferase (GART) preventing de novo purine synthesis, inhibiting DNA synthesis, arresting cells in the S phase of the cell cycle, and inhibiting tumor cell proliferation. Glycinamide ribonucleotide formyltransferase (GART) is a folate-dependent enzyme required for de novo purine synthesis. 

Overview of Clinical Research

Lometrexol is a DNA synthesis inhibitor, phosphoribosylglycinamide formyltransferase inhibitors and tetrahydrofolate dehydrogenase inhibitor. It has been used in trials studying the treatment of Lung Cancer, Drug/Agent Toxicity by Tissue/Organ, and Unspecified Adult Solid Tumor.

Reference

1. Curr Opin Oncol. 1991 Dec;3(6):1037-42. doi: 10.1097/00001622-199112000-00011.Novel chemotherapeutic agents in clinical development.Erlichman C(1).

 

The development of new chemotherapeutic agents for cancer treatment is pursued with the hope of finding compounds with novel chemical characteristics, unique mechanisms of action, and with improved therapeutic indexes. Seven novel agents at different stages of clinical development have been selected for review. D1694 is a thymidylate synthase inhibitor that has intriguing preclinical activity. The anthrapyrazoles consist of three analogues that are undergoing phase II testing at present. One of these agents, CI-941, has been reported to have significant clinical activity in breast cancer. Lometrexol is an inhibitor of glycinamide ribonuclide transformylase, a critical enzyme in purine biosynthesis, that is undergoing phase II testing. Taxotere, a semisynthetic analogue of taxol that stabilizes microtubules, is currently undergoing phase I testing. Gemcitabine, a fluorinated analogue of deoxycytidine that can inhibit ribonucleotide reductase and be incorporated into DNA, is undergoing phase II testing. BMY-25067 is a mitomycin C analogue that is less myelosuppressive and more active than mitomycin C in preclinical models. Topotecan, a topoisomerase I inhibitor, has been shown to cause myelosuppression as the dose-limiting toxicity in phase I testing. Although each of these agents have some unique and novel characteristics that merit their clinical testing, these agents' long-range clinical role will depend on their efficacy in randomized phase III comparative trials.

 

2. Curr Oncol Rep. 2003 Mar;5(2):114-25. doi: 10.1007/s11912-003-0098-3.Novel antifolate drugs.Purcell WT(1), Ettinger DS.

 

Antimetabolites are active chemotherapeutic agents for many solid tumor and hematologic malignancies. Folate antagonists, purine analogues, and pyrimidine analogues are the three main categories of antimetabolites. Methotrexate, the most studied folate antagonist, is effective in many malignancies. Methotrexate inhibits dihydrofolate reductase, which leads to accumulation of polyglutamated folates, causing further inhibition of thymidylate synthase and glycinamide ribonucleotide formyltransferase. Subsequently, the lack of reduced folate substrates impairs synthesis of purine nucleotides, thymidylate, and certain amino acids, which can lead to cell death. However, methotrexate resistance 

develops through several mechanisms, including decreased folate carrier-mediated membrane transport, dihydrofolate reductase gene amplification, specific transcription-translational modifications, and downregulation of intracellular methotrexate polyglutamation. Antifolate drug development has focused on agents designed to overcome different aspects of methotrexate resistance. This article reviews the enzymatic targets for antifolates, describes the known mechanisms of antifolate resistance, and summarizes the current development of novel antifolate agents. Discussed specifically are trimetrexate, edatrexate, raltitrexed, pemetrexed, ZD9331, lometrexol, LY309887, GW1843, OSI-7904(L), and nolatrexed, all of which have unique clinical pharmacology and are in various stages of development. The toxicity of antifolates has been sporadic and difficult to predict clinically. Supplementation with folic acid and vitamin B(12) has been shown to reduce the toxicity of pemetrexed without affecting efficacy and has increased the therapeutic index for this novel agent.