10-Formyl-5,10-dideaza-acyclic-5,6,7,8-tetrahydrofolic acid (10-Formyl-DDACTHF)

Marsilje, Thomas H.; Labroli, Marc; Hedrick, Michael; Jin, Qiong‐Hua; Desharnais, Joel; Baker, Stephen J.; Gooljarsingh, Lata T.; Ramcharan, Joseph; Tavassoli, Ali; Zhang, Yan; Wilson, Ian A.; Beardsley, G. Peter; Benkovic, Stephen J.; Boger, Dale L.

doi:10.1016/s0968-0896(02)00102-5

Cited by 15 publications

(22 citation statements)

References 84 publications

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“…N5-substituted MTHFS inhibitors, including 5-formylTHHF, are not attractive in vivo inhibitors because they can be phosphorylated and slowly metabolized by some mammalian MTHFS enzymes and because they are not effective substrates for folylpolyglutamate synthetase (1). A number of GARFT inhibitors have been synthesized (4,8,41,42), including 5,10-dideazatetrahydrofolate (DDATHF or Lometrexol). DDATHF inhibited mouse GARFT with a K i of 6 nM and human GARFT with a K i of 60 nM.…”

Section: Discussionmentioning

confidence: 99%

“…A similar compound, 10-formyl-5,10-dideazaacyclicTHF (10-formyl-DDACTHF), was shown to exhibit some selectivity for GARFT. 10-Formyl-DDACTHF is a substrate for folylpolyglutamate synthetase and accumulates in cell cultures over 100-fold (41). The pentaglutamate form effectively inhibits GARFT (K i , 14 nM) and was an effective cytotoxic agent (IC 50 , 60 nM).…”

Section: Discussionmentioning

confidence: 99%

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Regulation of de Novo Purine Biosynthesis by Methenyltetrahydrofolate Synthetase in Neuroblastoma

Field

Szebenyi

Stover

2006

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Regulation of de Novo Purine Biosynthesis by Methenyltetrahydrofolate Synthetase in Neuroblastoma

Field

Szebenyi

Stover

2006

Journal of Biological Chemistry

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“…The diaminopyrimidinone ring makes up to six hydrogen bonds to the main-chain amides and carbonyl oxygens of Arg90, Leu92, Ala140, Glu141 and two hydrogen bonds with structurally ordered waters in a water-mediated network (Figure 5). Previous studies and in vitro growth inhibition experiments showed that the diaminopyrimidinone ring (seen in compounds 5–8 ) is favored over the quinazoline ring (seen in 4 ) (15) . The diaminopyrimidinone ring of 10 R 7 and 10 S 8 contains a nitrogen atom at the N8 position, similar to that of the natural cofactor 2 and 3 (also conserved in 9–11 ).…”

Section: Resultsmentioning

confidence: 99%

“…Enzyme activity assays of recombinant hGAR Tfase and recombinant human aminoimidazole carboxamide ribonucleotide transformylase (hAICAR Tfase) were performed as previously described (15, 41) . Kinetics of the enzyme reactions were monitored for 2 min after reaction initiation.…”

Section: Methodsmentioning

confidence: 99%

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Biological and Structural Evaluation of 10R- and 10S-Methylthio-DDACTHF Reveals a New Role for Sulfur in Inhibition of Glycinamide Ribonucleotide Transformylase

et al. 2013

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Glycinamide ribonucleotide transformylase (GAR Tfase) is a folate-dependent enzyme in the de novo purine biosynthesis pathway, which has long been considered a potential target for development of anti-neoplastic therapeutics. Here we report the biological and X-ray crystallographic evaluations of both independent C10 diastereomers 10S and 10R methylthio-DDACTHF bound to human GAR Tfase, including the highest resolution apo GAR Tfase structure to date (1.52 Å). Both diastereomers are potent inhibitors (10R Ki = 210 nM, 10S Ki = 180 nM) of GAR Tfase and exhibit effective inhibition of human leukemia cell growth (IC50 = 80 and 50 nM, respectively). Their inhibitory activity was surprisingly high and these lipophilic C10-substituted analogs show distinct advantages over their hydrophilic counterparts, most strikingly in retaining potency in mutant human leukemia cell lines that lack reduced folate carrier protein activity (IC50 = 70 and 60 nM, respectively). Structural characterization reveals a new binding mode for these diasterisomers, in which the lipophilic thiomethyl groups penetrate deeper into a hydrophobic pocket within the folate-binding site. In silico docking simulations of three other sulfur-containing folate analogs also indicates that this hydrophobic cleft represents a favorable region for binding lipophilic substituents. Overall, these results suggest sulfur and its substitutions play an important role in not only the binding of anti-folates to GAR Tfase, but also in selectivity and cellular activity (growth inhibition), thereby presenting new possibilities for future design of potent and selective anti-folate drugs that target GAR Tfase.

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Targeting Tumour Proliferation with a Small‐Molecule Inhibitor of AICAR Transformylase Homodimerization

et al. 2012

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Aminoimidazole carboxamide ribonucleotide transformylase/inosine monophosphate cyclohydrolase (ATIC) is a bifunctional homodimeric enzyme that catalyses the last two steps of de novo purine biosynthesis. Homodimerization of ATIC, a protein-protein interaction with an interface of over 5000 Å2, is required for its aminoimidazole carboxamide ribonucleotide (AICAR) transformylase activity, with the active sites forming at the interface of the interacting proteins. Here, we report the development of a small-molecule inhibitor of AICAR transformylase that functions by preventing the homodimerization of ATIC. The compound is derived from a previously reported cyclic hexa-peptide inhibitor of AICAR transformylase (with a Ki of 17 μM), identified by high-throughput screening. The active motif of the cyclic peptide is identified as an arginine-tyrosine dipeptide, a capped analogue of which inhibits AICAR transformylase with a Ki of 84 μM. A library of non-natural analogues of this dipeptide was designed, synthesized, and assayed. The most potent compound inhibits AICAR transformylase with a Ki of 685 nM, a 25-fold improvement in activity from the parent cyclic peptide. The potential for this AICAR transformylase inhibitor in cancer therapy is assessed by studying its effect on the proliferation of a model breast cancer cell line. Using a non-radioactive proliferation assay and live cell imaging, a dose-dependent reduction in cell numbers and cell division rates was observed in cells treated with our ATIC dimerization inhibitor.

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10-Formyl-5,10-dideaza-acyclic-5,6,7,8-tetrahydrofolic acid (10-Formyl-DDACTHF)

Cited by 15 publications

References 84 publications

Regulation of de Novo Purine Biosynthesis by Methenyltetrahydrofolate Synthetase in Neuroblastoma

Regulation of de Novo Purine Biosynthesis by Methenyltetrahydrofolate Synthetase in Neuroblastoma

Biological and Structural Evaluation of 10R- and 10S-Methylthio-DDACTHF Reveals a New Role for Sulfur in Inhibition of Glycinamide Ribonucleotide Transformylase

Targeting Tumour Proliferation with a Small‐Molecule Inhibitor of AICAR Transformylase Homodimerization

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