lometrexol and nolatrexed

Many novel antifolate compounds with unique pharmacologic properties are currently in clinical development. These newer antifolates differ from methotrexate, the most widely used and studied drug in this class, in terms of their lipid solubility and cellular transport affinity, their level of polyglutamation, and their specificity for inhibiting folate-dependent enzymes, such as dihydrofolate reductase, thymidylate synthase, or glycinamide ribonucleotide formyltransferase. The current status (ie, mechanism of action, clinical response rates, and toxicity) of some of the newer antifolate compounds presently in clinical testing, including edatrexate, piritrexim, raltritrexed, LY 231514, AG337, AG331, 1843U89, ZD 9331, and lometrexol, is reviewed.

Topics: Aminopterin; Animals; Antimetabolites, Antineoplastic; Clinical Trials as Topic; Drug Design; Enzyme Inhibitors; Folic Acid Antagonists; Glutamates; Guanine; Humans; Indoles; Isoindoles; Pemetrexed; Pyrimidines; Quinazolines; Tetrahydrofolates; Thiophenes; Thymidylate Synthase

Metabolic reprogramming of tumor cells toward serine catabolism is now recognized as a hallmark of cancer. Serine hydroxymethyltransferase (SHMT), the enzyme providing one-carbon units by converting serine and tetrahydrofolate (H4 PteGlu) to glycine and 5,10-CH2 -H4 PteGlu, therefore represents a target of interest in developing new chemotherapeutic drugs. In this study, 13 folate analogues under clinical evaluation or in therapeutic use were in silico screened against SHMT, ultimately identifying four antifolate agents worthy of closer evaluation. The interaction mode of SHMT with these four antifolate drugs (lometrexol, nolatrexed, raltitrexed, and methotrexate) was assessed. The mechanism of SHMT inhibition by the selected antifolate agents was investigated in vitro using the human cytosolic isozyme. The results of this study showed that lometrexol competitively inhibits SHMT with inhibition constant (Ki ) values in the low micromolar. The binding mode of lometrexol to SHMT was further investigated by molecular docking. These results thus provide insights into the mechanism of action of antifolate drugs and constitute the basis for the rational design of novel and more potent inhibitors of SHMT.

Topics: Folic Acid Antagonists; Glycine Hydroxymethyltransferase; Humans; Methotrexate; Molecular Docking Simulation; Quinazolines; Tetrahydrofolates; Thiophenes

Since the clinical introduction of the antifolates aminopterin (AMT) and methotrexate (MTX) many promising analogs have been developed. A common feature of these compounds is their ability to induce bone marrow suppression. However, few studies have been undertaken on the effect of the folic acid analogs on the cells comprising the hematopoietic system.. In this paper we describe the effects of the novel thymidylate synthase (TS) inhibitors raltitrexed (Tomudex, ZD1694), AG337 (nolatrexed, Thymitaq), and the two closely related analogs 5,8-dideazaisofolic acid (IAHQ2a) and 2-desamino-2-methyl 5,8-dideazaisofolic acid (IAHQ2c), the glycinamide-ribonucleosyl (GAR) transformylase inhibitor lometrexol (DDATHF), and the dihydrofolate reductase (DHFR) inhibitors MTX, AMT, trimetrexate (TMTX), and edatrexate (EDX) on purified populations of early and late murine hematopoietic progenitor cells.. All the antifolates inhibited bone marrow proliferation in suspension cultures and all drugs except DDATHF inhibited colony formation by more mature progenitor cells (CFU-C) in clonogenic assays. The lipophilic agents TMTX and AG337 were most toxic, totally abolishing CFU-C colony formation at high concentrations. When IAHQ2c, raltitrexed, DDATHF, and MTX were investigated further for effects on the immature high proliferative potential colony-forming cells (HPP-CFCs) in semisolid and limiting dilution cultures, none of these agents were found to be toxic to the HPP-CFC, but induced a reversible developmental arrest in the progenitor cell population.

Topics: Aminopterin; Animals; Cell Division; Cells, Cultured; Enzyme Inhibitors; Female; Folic Acid; Folic Acid Antagonists; Hematopoietic Stem Cells; Methotrexate; Mice; Mice, Inbred BALB C; Quinazolines; Tetrahydrofolates; Thiophenes; Trimetrexate