Page last updated: 2024-10-15

1843u89

Description

1843U89: structure given in first source; a folate analog [Medical Subject Headings (MeSH), National Library of Medicine, extracted Dec-2023]

Cross-References

ID SourceID
PubMed CID135403832
CHEMBL ID169896
SCHEMBL ID1649579
SCHEMBL ID6064518
MeSH IDM0213039

Synonyms (48)

Synonym
(s)-2-{5-[(3-methyl-1-oxo-1,2-dihydro-benzo[f]quinazolin-9-ylmethyl)-amino]-1-oxo-1,3-dihydro-isoindol-2-yl}-pentanedioic acid
bdbm50040861
s)-2-(5(((1,2-dihydro-3-methyl-1-oxobenzo(f)quinazolin-9-yl)methyl)amino)1-oxo-2-isoindolinyl)glutaric acid
F89 ,
139987-54-5
gw1843
1843u89
(s)-2-(5-(((1,2-dihydro-3-methyl-1-oxobenzo(f)quinazolin-9-yl)methyl)amino)1-oxo-2-isoindolinyl)glutaric acid
1F28
2-(5-(((1,2-dihydro-3-methyl-1-oxobenzo(f)quinazolin-9-yl)methyl)amino)-1-oxo-2-isoindolinyl)glutaric acid
osi 7904l
bw 1843u89
1843u
osi-7904l
pentanedioic acid, 2-(5-(((1,2-dihydro-3-methyl-1-oxobenzo(f)quinazolin-9-yl)methyl)amino)-1,3-dihydro-1-oxo-2h-isoindol-2-yl)-, (s)-
bw-1843u89
TCMDC-131928 ,
(2s)-2-[6-[(3-methyl-1-oxo-4h-benzo[f]quinazolin-9-yl)methylamino]-3-oxo-1h-isoindol-2-yl]pentanedioic acid
osi-7904
osi 7904
gw-1843
CHEMBL169896 ,
on177zce7m ,
unii-on177zce7m
u89 compound
pentanedioic acid, 2-(5-(((1,2-dihydro-3-methyl-1-oxobenzo(f)quinazolin-9-yl)methyl)amino)-1,3-dihydro-1-oxo-2h-isoindol-2-yl)-, (2s)-
osi 7904l [who-dd]
osi 7904 [who-dd]
SCHEMBL1649579
SCHEMBL6064518
BRVFNEZMTRVUGW-QFIPXVFZSA-N
(s)-2-(5-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-1-oxo-2-isoindolinyl) glutaric acid
(s)-2-(5-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-1-oxo-2-isoindolinyl)glutaric acid
gw1843u89
(s)-2-(5-(((1,2-dihydro3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)ami-no)-1-oxo-2-isoindolinyl)glutaric acid
(s)-2-(5-(((3-methyl-1-oxo-1,2-dihydrobenzo[f]quinazolin-9-yl)methyl)amino)-1-oxoisoindolin-2-yl)pentanedioic acid
AKOS025290741
(2s)-2-[6-[(3-methyl-1-oxo-2h-benzo[f]quinazolin-9-yl)methylamino]-3-oxo-1h-isoindol-2-yl]pentanedioic acid
mfcd00871785
AS-50416
(2s)-2-[5-[[(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl]amino]-1,3-dihydro-1-oxo-2h-isoindol-2-yl]pentanedioic acid
DTXSID70930683
(2s)-2-(5-{[(3-methyl-1-oxo-1,2-dihydrobenzo[f]quinazolin-9-yl)methyl]amino}-1-oxo-1,3-dihydro-2h-isoindol-2-yl)pentanedioic acid
osi-7904l free acid
Q27285738
P10154
(s)-2-(5-(((3-methyl-1-oxo-1,2-dihydrobenzo[f]quinazolin-9-yl)methyl)amino)-1-oxoisoindolin-2-yl)pentanedioicacid
AKOS040746187

Research Excerpts

Overview

1843U89 is a potent inhibitor (Ki = 0.09 nM) of thymidylate synthase (TS; EC 2.1.45) that is in clinical trial for the treatment of solid tumors.

ExcerptReference
"1843U89 is a potent inhibitor (Ki = 0.09 nM) of thymidylate synthase (TS; EC 2.1.1.45) that is in clinical trial for the treatment of solid tumors. "( In vitro uptake, anabolism, and cellular retention of 1843U89 and other benzoquinazoline inhibitors of thymidylate synthase.
Ferone, R; Hanlon, MH, 1996
)

Toxicity

ExcerptReference
" OSI-7904L was much more toxic than OSI-7904 in the mouse with primary toxicities to the intestines, bone marrow, and thymus."( Pharmacokinetics, safety, and efficacy of a liposome encapsulated thymidylate synthase inhibitor, OSI-7904L [(S)-2-[5-[(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl]amino-1-oxo-2-isoindolynl]-glutaric acid] in mice.
Abbott, E; Brown, EN; Colagiovanni, DB; Desjardins, J; Drolet, DW; Emerson, DL, 2004
)

Pharmacokinetics

ExcerptReference
" The pharmacokinetics of the classical antifolate methotrexate have been well-defined and pharmacokinetic data can be exploited to reduce the toxicity and enhance the activity of the drug."( Clinical pharmacokinetics of antitumor antifolates.
Newell, DR, 1999
)
" The study also sought to characterize the pharmacokinetic behavior of 1843U89 and to seek preliminary evidence of anticancer activity."( A phase I and pharmacokinetic study of 1843U89, a noncompetitive inhibitor of thymidylate synthase, in patients with advanced solid malignancies.
Burris, H; Goetz, A; Hohneker, JA; Johnson, TR; Lampkin, T; Rowinsky, EK; Sailstad, J; Schwartz, G; Smetzer, L; Von Hoff, DD, 2001
)

Bioavailability

ExcerptReference
" Previous drug design efforts based on co-factor analogues have produced good inhibitors of TS, but poor bioavailability and toxicity have limited their usefulness."( The complex of the anti-cancer therapeutic, BW1843U89, with thymidylate synthase at 2.0 A resolution: implications for a new mode of inhibition.
Stout, TJ; Stroud, RM, 1996
)
[information is derived through text-mining from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Protein Targets (7)

Inhibition Measurements

ProteinTaxonomyMeasurementAverageMin (ref.)Avg (ref.)Max (ref.)Bioassay(s)
Chain A, THYMIDYLATE SYNTHASEPneumocystis cariniiKi0.01600.01600.01600.0160AID977610
Thymidylate synthase Escherichia coli LF82IC50 (µMol)0.02300.02300.03550.0480AID613094
Dihydrofolate reductaseHomo sapiens (human)IC50 (µMol)20.00000.00060.87267.3000AID613096
Thymidylate synthaseHomo sapiens (human)IC50 (µMol)0.03200.00662.06379.5000AID613093
Thymidylate synthaseHomo sapiens (human)Ki0.00010.00010.34353.0000AID212325; AID613099
Dihydrofolate reductaseEscherichia coli K-12IC50 (µMol)20.00000.00150.55126.8000AID613097
Bifunctional dihydrofolate reductase-thymidylate synthaseToxoplasma gondiiIC50 (µMol)0.36850.00061.042810.0000AID613095; AID613098
[prepared from compound, protein, and bioassay information from National Library of Medicine (NLM), extracted Dec-2023]

Other Measurements

ProteinTaxonomyMeasurementAverageMin (ref.)Avg (ref.)Max (ref.)Bioassay(s)
Folylpolyglutamate synthase, mitochondrialHomo sapiens (human)Km0.40000.40004.53447.3000AID71224
[prepared from compound, protein, and bioassay information from National Library of Medicine (NLM), extracted Dec-2023]

Biological Processes (40)

Processvia Protein(s)Taxonomy
tetrahydrobiopterin biosynthetic processDihydrofolate reductaseHomo sapiens (human)
one-carbon metabolic processDihydrofolate reductaseHomo sapiens (human)
negative regulation of translationDihydrofolate reductaseHomo sapiens (human)
axon regenerationDihydrofolate reductaseHomo sapiens (human)
response to methotrexateDihydrofolate reductaseHomo sapiens (human)
dihydrofolate metabolic processDihydrofolate reductaseHomo sapiens (human)
tetrahydrofolate metabolic processDihydrofolate reductaseHomo sapiens (human)
tetrahydrofolate biosynthetic processDihydrofolate reductaseHomo sapiens (human)
folic acid metabolic processDihydrofolate reductaseHomo sapiens (human)
positive regulation of nitric-oxide synthase activityDihydrofolate reductaseHomo sapiens (human)
regulation of removal of superoxide radicalsDihydrofolate reductaseHomo sapiens (human)
dTMP biosynthetic processThymidylate synthaseHomo sapiens (human)
dTTP biosynthetic processThymidylate synthaseHomo sapiens (human)
circadian rhythmThymidylate synthaseHomo sapiens (human)
response to xenobiotic stimulusThymidylate synthaseHomo sapiens (human)
response to toxic substanceThymidylate synthaseHomo sapiens (human)
negative regulation of translationThymidylate synthaseHomo sapiens (human)
uracil metabolic processThymidylate synthaseHomo sapiens (human)
methylationThymidylate synthaseHomo sapiens (human)
response to progesteroneThymidylate synthaseHomo sapiens (human)
response to vitamin AThymidylate synthaseHomo sapiens (human)
response to cytokineThymidylate synthaseHomo sapiens (human)
tetrahydrofolate interconversionThymidylate synthaseHomo sapiens (human)
response to ethanolThymidylate synthaseHomo sapiens (human)
response to organophosphorusThymidylate synthaseHomo sapiens (human)
developmental growthThymidylate synthaseHomo sapiens (human)
cartilage developmentThymidylate synthaseHomo sapiens (human)
response to glucocorticoidThymidylate synthaseHomo sapiens (human)
response to folic acidThymidylate synthaseHomo sapiens (human)
intestinal epithelial cell maturationThymidylate synthaseHomo sapiens (human)
DNA biosynthetic processThymidylate synthaseHomo sapiens (human)
liver regenerationThymidylate synthaseHomo sapiens (human)
10-formyltetrahydrofolate biosynthetic processDihydrofolate reductaseEscherichia coli K-12
response to xenobiotic stimulusDihydrofolate reductaseEscherichia coli K-12
folic acid biosynthetic processDihydrofolate reductaseEscherichia coli K-12
one-carbon metabolic processDihydrofolate reductaseEscherichia coli K-12
response to methotrexateDihydrofolate reductaseEscherichia coli K-12
tetrahydrofolate biosynthetic processDihydrofolate reductaseEscherichia coli K-12
response to antibioticDihydrofolate reductaseEscherichia coli K-12
dihydrofolate metabolic processDihydrofolate reductaseEscherichia coli K-12
folic acid metabolic processDihydrofolate reductaseEscherichia coli K-12
liver developmentFolylpolyglutamate synthase, mitochondrialHomo sapiens (human)
nucleobase-containing compound metabolic processFolylpolyglutamate synthase, mitochondrialHomo sapiens (human)
glutamate metabolic processFolylpolyglutamate synthase, mitochondrialHomo sapiens (human)
one-carbon metabolic processFolylpolyglutamate synthase, mitochondrialHomo sapiens (human)
folic acid-containing compound metabolic processFolylpolyglutamate synthase, mitochondrialHomo sapiens (human)
animal organ regenerationFolylpolyglutamate synthase, mitochondrialHomo sapiens (human)
folic acid metabolic processFolylpolyglutamate synthase, mitochondrialHomo sapiens (human)
tetrahydrofolylpolyglutamate biosynthetic processFolylpolyglutamate synthase, mitochondrialHomo sapiens (human)
[Information is prepared from geneontology information from the June-17-2024 release]

Molecular Functions (17)

Processvia Protein(s)Taxonomy
mRNA regulatory element binding translation repressor activityDihydrofolate reductaseHomo sapiens (human)
mRNA bindingDihydrofolate reductaseHomo sapiens (human)
dihydrofolate reductase activityDihydrofolate reductaseHomo sapiens (human)
folic acid bindingDihydrofolate reductaseHomo sapiens (human)
NADPH bindingDihydrofolate reductaseHomo sapiens (human)
sequence-specific mRNA bindingDihydrofolate reductaseHomo sapiens (human)
NADP bindingDihydrofolate reductaseHomo sapiens (human)
mRNA regulatory element binding translation repressor activityThymidylate synthaseHomo sapiens (human)
thymidylate synthase activityThymidylate synthaseHomo sapiens (human)
folic acid bindingThymidylate synthaseHomo sapiens (human)
protein homodimerization activityThymidylate synthaseHomo sapiens (human)
sequence-specific mRNA bindingThymidylate synthaseHomo sapiens (human)
dihydrofolate reductase activityDihydrofolate reductaseEscherichia coli K-12
protein bindingDihydrofolate reductaseEscherichia coli K-12
folic acid bindingDihydrofolate reductaseEscherichia coli K-12
oxidoreductase activityDihydrofolate reductaseEscherichia coli K-12
NADP bindingDihydrofolate reductaseEscherichia coli K-12
methotrexate bindingDihydrofolate reductaseEscherichia coli K-12
dihydrofolic acid bindingDihydrofolate reductaseEscherichia coli K-12
NADP+ bindingDihydrofolate reductaseEscherichia coli K-12
NADPH bindingDihydrofolate reductaseEscherichia coli K-12
tetrahydrofolylpolyglutamate synthase activityFolylpolyglutamate synthase, mitochondrialHomo sapiens (human)
ATP bindingFolylpolyglutamate synthase, mitochondrialHomo sapiens (human)
metal ion bindingFolylpolyglutamate synthase, mitochondrialHomo sapiens (human)
[Information is prepared from geneontology information from the June-17-2024 release]

Ceullar Components (6)

Processvia Protein(s)Taxonomy
mitochondrionDihydrofolate reductaseHomo sapiens (human)
cytosolDihydrofolate reductaseHomo sapiens (human)
mitochondrionDihydrofolate reductaseHomo sapiens (human)
nucleusThymidylate synthaseHomo sapiens (human)
cytoplasmThymidylate synthaseHomo sapiens (human)
mitochondrionThymidylate synthaseHomo sapiens (human)
mitochondrial inner membraneThymidylate synthaseHomo sapiens (human)
mitochondrial matrixThymidylate synthaseHomo sapiens (human)
cytosolThymidylate synthaseHomo sapiens (human)
mitochondrionThymidylate synthaseHomo sapiens (human)
cytosolThymidylate synthaseHomo sapiens (human)
cytosolDihydrofolate reductaseEscherichia coli K-12
cytosolDihydrofolate reductaseEscherichia coli K-12
mitochondrial inner membraneFolylpolyglutamate synthase, mitochondrialHomo sapiens (human)
mitochondrial matrixFolylpolyglutamate synthase, mitochondrialHomo sapiens (human)
cytosolFolylpolyglutamate synthase, mitochondrialHomo sapiens (human)
cytoplasmFolylpolyglutamate synthase, mitochondrialHomo sapiens (human)
mitochondrionFolylpolyglutamate synthase, mitochondrialHomo sapiens (human)
cytosolFolylpolyglutamate synthase, mitochondrialHomo sapiens (human)
[Information is prepared from geneontology information from the June-17-2024 release]

Bioassays (21)

Assay IDTitleYearJournalArticle
AID1159586Biochemical screen of P. falciparum PK62016PloS one, , Volume: 11, Issue:3
Biochemical Screening of Five Protein Kinases from Plasmodium falciparum against 14,000 Cell-Active Compounds.
AID1159585Biochemical screen of P. falciparum CDPK12016PloS one, , Volume: 11, Issue:3
Biochemical Screening of Five Protein Kinases from Plasmodium falciparum against 14,000 Cell-Active Compounds.
AID1159589Biochemical screen of P. falciparum MAPK22016PloS one, , Volume: 11, Issue:3
Biochemical Screening of Five Protein Kinases from Plasmodium falciparum against 14,000 Cell-Active Compounds.
AID1159588Biochemical screen of P. falciparum CDPK42016PloS one, , Volume: 11, Issue:3
Biochemical Screening of Five Protein Kinases from Plasmodium falciparum against 14,000 Cell-Active Compounds.
AID1159587Biochemical screen of P. falciparum PK72016PloS one, , Volume: 11, Issue:3
Biochemical Screening of Five Protein Kinases from Plasmodium falciparum against 14,000 Cell-Active Compounds.
AID613094Inhibition of Escherichia coli TS assessed as oxidation of tetrahydrofolate to dihydrofolate after 2 to 12 mins by spectrophotometry2011Bioorganic & medicinal chemistry, Jun-01, Volume: 19, Issue:11
Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors.
AID613095Inhibition of Toxoplasma gondii TS assessed as oxidation of tetrahydrofolate to dihydrofolate after 2 to 12 mins by spectrophotometry2011Bioorganic & medicinal chemistry, Jun-01, Volume: 19, Issue:11
Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors.
AID71224Substrate selectivity for hog liver Folyl-polyglutamate synthase1994Journal of medicinal chemistry, Mar-18, Volume: 37, Issue:6
Benzo[f]quinazoline inhibitors of thymidylate synthase: methyleneamino-linked aroylglutamate derivatives.
AID212325The compound was tested for inhibitory activity against thymidylate synthase (purified recombinant human gene) from Escherichia coli1994Journal of medicinal chemistry, Mar-18, Volume: 37, Issue:6
Benzo[f]quinazoline inhibitors of thymidylate synthase: methyleneamino-linked aroylglutamate derivatives.
AID201691The compound was tested for growth inhibition against SW 480 colon adenocarcinoma tumor cells1994Journal of medicinal chemistry, Mar-18, Volume: 37, Issue:6
Benzo[f]quinazoline inhibitors of thymidylate synthase: methyleneamino-linked aroylglutamate derivatives.
AID613098Inhibition of Toxoplasma gondii DHFR by spectrophotometry2011Bioorganic & medicinal chemistry, Jun-01, Volume: 19, Issue:11
Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors.
AID613093Inhibition of human TS assessed as oxidation of tetrahydrofolate to dihydrofolate after 2 to 12 mins by spectrophotometry2011Bioorganic & medicinal chemistry, Jun-01, Volume: 19, Issue:11
Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors.
AID71225Substrate selectivity for hog liver Folyl-polyglutamate synthase was assessed from Vm1994Journal of medicinal chemistry, Mar-18, Volume: 37, Issue:6
Benzo[f]quinazoline inhibitors of thymidylate synthase: methyleneamino-linked aroylglutamate derivatives.
AID613096Inhibition of human DHFR by spectrophotometry2011Bioorganic & medicinal chemistry, Jun-01, Volume: 19, Issue:11
Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors.
AID230662Ratio of Vm and Km values, a measure of Substrate selectivity for hog liver folyl-poly-glutamate synthetase1994Journal of medicinal chemistry, Mar-18, Volume: 37, Issue:6
Benzo[f]quinazoline inhibitors of thymidylate synthase: methyleneamino-linked aroylglutamate derivatives.
AID103522The compound was tested for growth inhibition against MCF-7 breast adenocarcinoma tumor cells1994Journal of medicinal chemistry, Mar-18, Volume: 37, Issue:6
Benzo[f]quinazoline inhibitors of thymidylate synthase: methyleneamino-linked aroylglutamate derivatives.
AID613097Inhibition of Escherichia coli DHFR by spectrophotometry2011Bioorganic & medicinal chemistry, Jun-01, Volume: 19, Issue:11
Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors.
AID105476Inhibition of MTX uptake in MOLT-4 human T-cell leukemia cells1994Journal of medicinal chemistry, Mar-18, Volume: 37, Issue:6
Benzo[f]quinazoline inhibitors of thymidylate synthase: methyleneamino-linked aroylglutamate derivatives.
AID613099Inhibition of TS by spectrophotometry2011Bioorganic & medicinal chemistry, Jun-01, Volume: 19, Issue:11
Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors.
AID977610Experimentally measured binding affinity data (Ki) for protein-ligand complexes derived from PDB2001Chemistry & biology, May, Volume: 8, Issue:5
Approaches to solving the rigid receptor problem by identifying a minimal set of flexible residues during ligand docking.
AID1811Experimentally measured binding affinity data derived from PDB2001Chemistry & biology, May, Volume: 8, Issue:5
Approaches to solving the rigid receptor problem by identifying a minimal set of flexible residues during ligand docking.
[information is prepared from bioassay data collected from National Library of Medicine (NLM), extracted Dec-2023]

Research

Studies (36)

TimeframeStudies, This Drug (%)All Drugs %
pre-19900 (0.00)18.7374
1990's25 (69.44)18.2507
2000's9 (25.00)29.6817
2010's2 (5.56)24.3611
2020's0 (0.00)2.80
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Study Types

Publication TypeThis drug (%)All Drugs (%)
Trials1 (2.70%)5.53%
Reviews5 (13.51%)6.00%
Case Studies0 (0.00%)4.05%
Observational0 (0.00%)0.25%
Other31 (83.78%)84.16%
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]