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Chemical Compound Review

CHEMBL389051     (2S)-2-[[4-[(2-amino-4-oxo- 1H-quinazolin-6...

Synonyms: TCMDC-131823, CHEBI:41452, CB-3717, CHEBI:474002, AC1L9EKK, ...
 
 
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Disease relevance of AIDS106597

 

High impact information on AIDS106597

  • Similar patterns were seen in this line upon treatment with CB3717 or aphidicolin, indicating that this fragmentation pattern is not specific to TS inhibition and may be characteristic of a more general response than that seen in the other two cell lines [6].
  • The same drug sensitivity profile was observed for KB cells, with the exception that these cells were also sensitive to growth inhibition by CB3717 but only in folate-conditioned medium [7].
  • Similar results were obtained using two quinazoline-based inhibitors of thymidylate synthase, N10-propargyl-5,8-dideazafolic acid (CB3717) and ICI M247496 [8].
  • Trimetrexate (TMTX), 5,10-dideazatetrahydrofolate (DDATHF), and 10-propargyl-5,8-dideazafolate (PDDF, CB3717) are antifolates whose primary intracellular targets are dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, and thymidylate synthase, respectively [9].
  • This high sensitivity was related to a high affinity of the FBP for CB3717 and ICI-198,583 (Kd 2-3 nM), which is only 3-fold lower than for folic acid (Kd 1 nM) but significantly higher than for MTX (Kd 100 nM) [10].
 

Chemical compound and disease context of AIDS106597

 

Biological context of AIDS106597

  • Finally, the structure shows a unique conformation for the cofactor analog, CB3717, which has implications for structure-based drug design and sheds light on the controversy surrounding the previously observed enzymatic nonidentity between the chemically identical monomers of the TS dimer [14].
  • The second crystals contained both dUMP and CB3717 in the active site, but Glu 126 formed three hydrogen bonds to nearby residues (two through water) and was in a position that partially overlapped with the normal phosphate binding site, resulting in a approximately 1 A shift in the phosphate group [15].
  • Treatment of cells for 16 hr at an IC50 concentration of CB3717 caused a decrease of 88% in cellular dTTP and a 2,300% increase in dUMP [16].
  • In contrast, levels of CB3717 tetra and pentaglutamates declined solely due to dilution during cell division [17].
  • To assess these effects, and further define the time course and dose relationship of CB3717-induced renal damage, an assay of glomerular filtration rate (GFR) has been developed which can be used in mice and hence in the screening of novel compounds [18].
 

Anatomical context of AIDS106597

  • These results suggest that CB3717 may be a useful new therapeutic agent in human primary liver cell carcinoma and that blocking the salvage pathway may further increase efficacy [19].
  • In addition to CB3717, a metabolite was detected in the feces which comprised 8% of the dose administered [20].
 

Associations of AIDS106597 with other chemical compounds

  • Growth-inhibition studies identified a series of drugs that were preferentially transported via RFC (2,4-diamino structures) or mFBP (CB3717, 2-NH-ZD1694, or 5,8-dideazaisofolic acid), whereas other drugs were efficiently transported via both transport pathways (e.g., DDATHF, ZD1694, BW1843U89, or LY231514) [21].
  • It was observed that RFC exhibited an efficient substrate affinity for all analogues except CB3717, 2-NH2-ZD1694, and glutamate side-chain-modified FPGS inhibitors [21].
  • Modifications to the bicyclic ring system of the potent thymidylate synthase (TS) inhibitor N-[4-[N-[(2-amino-3,4-dihydro-4-oxo-6- quinazolinyl)methyl]-N-prop-2-ynylamino]benzoyl]-L-glutamic acid (1, CB3717) have led to the synthesis of a series of quinoline antifolates bearing a variety of substituents at the C2 and C4 positions [22].
  • The cocrystal structure of TS from Pneumocystis carinii (PcTS), a new drug target for an important pathogen, with its substrate, deoxyuridine monophosphate (dUMP), and a cofactor mimic, CB3717, was determined [23].
  • In five pairs of acquired cisplatin-resistant human tumour cell lines (three ovarian, one cervical and one testicular) which encompass all of the main known mechanisms of platinum drug resistance, ZD1694, CB3717 and the DHFR inhibitor, methotrexate, all exhibited non-cross-resistance [24].
 

Gene context of AIDS106597

  • The highly MTX-resistant RAJI/MTX-R and WI-L2/m4 cells showed minor cross-resistance to the dual inhibitor of thymidylate synthetase and DHFR, CB3717 (5- and 15-fold, respectively) [1].
  • Compounds with increased selectivity for TS followed with the highly specific inhibitor, CB3717 being synthesised in 1979 at the Institute of Cancer Research (ICR) [25].
  • MOLT-3/TMQ200 cells displayed classical multidrug resistance; sequential development of CB3717 resistance in the TMQ-resistant cells resulted in an enhancement of the multidrug-resistance phenotype and a concomitant increase of MDR1 mRNA [26].
  • Increased thymidylate synthase in L1210 cells possessing acquired resistance to N10-propargyl-5,8-dideazafolic acid (CB3717): development, characterization, and cross-resistance studies [27].
  • However, a membrane-associated folate-binding protein (FBP) offers another route for entry of CB3717 and ICI-198,583 [10].
 

Analytical, diagnostic and therapeutic context of AIDS106597

References

  1. Patterns of cross-resistance to the antifolate drugs trimetrexate, metoprine, homofolate, and CB3717 in human lymphoma and osteosarcoma cells resistant to methotrexate. Diddens, H., Niethammer, D., Jackson, R.C. Cancer Res. (1983) [Pubmed]
  2. Quinazoline antifolates inhibiting thymidylate synthase: 2-desamino derivatives with enhanced solubility and potency. Jones, T.R., Thornton, T.J., Flinn, A., Jackman, A.L., Newell, D.R., Calvert, A.H. J. Med. Chem. (1989) [Pubmed]
  3. Cofactor triggers the conformational change in thymidylate synthase: implications for an ordered binding mechanism. Kamb, A., Finer-Moore, J.S., Stroud, R.M. Biochemistry (1992) [Pubmed]
  4. A C-terminal conformational equilibrium in thymidylate synthase observed by electron paramagnetic resonance spectroscopy. Carreras, C.W., Naber, N., Cooke, R., Santi, D.V. Biochemistry (1994) [Pubmed]
  5. Phase II study of the thymidylate synthetase inhibitor CB3717 (N10-propargyl-5,8-dideazafolic acid) in colorectal cancer. Harding, M.J., Cantwell, B.M., Milstead, R.A., Harris, A.L., Kaye, S.B. Br. J. Cancer (1988) [Pubmed]
  6. Variations in patterns of DNA damage induced in human colorectal tumor cells by 5-fluorodeoxyuridine: implications for mechanisms of resistance and cytotoxicity. Canman, C.E., Tang, H.Y., Normolle, D.P., Lawrence, T.S., Maybaum, J. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  7. Functional activity of the reduced folate carrier in KB, MA104, and IGROV-I cells expressing folate-binding protein. Westerhof, G.R., Rijnboutt, S., Schornagel, J.H., Pinedo, H.M., Peters, G.J., Jansen, G. Cancer Res. (1995) [Pubmed]
  8. bcl-2 modulation of apoptosis induced by anticancer drugs: resistance to thymidylate stress is independent of classical resistance pathways. Fisher, T.C., Milner, A.E., Gregory, C.D., Jackman, A.L., Aherne, G.W., Hartley, J.A., Dive, C., Hickman, J.A. Cancer Res. (1993) [Pubmed]
  9. Quantitation of folic acid enhancement of antifolate synergism. Gaumont, Y., Kisliuk, R.L., Parsons, J.C., Greco, W.R. Cancer Res. (1992) [Pubmed]
  10. Multiple membrane transport systems for the uptake of folate-based thymidylate synthase inhibitors. Jansen, G., Schornagel, J.H., Westerhof, G.R., Rijksen, G., Newell, D.R., Jackman, A.L. Cancer Res. (1990) [Pubmed]
  11. Potentiation of quinazoline antifolate (CB3717) toxicity by dipyridamole in human lung carcinoma, A549, cells. Curtin, N.J., Harris, A.L. Biochem. Pharmacol. (1988) [Pubmed]
  12. The efficacy of 5-fluorouracil in human colorectal cancer is not enhanced by thymidylate synthetase inhibition with CB3717 (N10-propargyl-5,8 dideazafolic acid). Cantwell, B.M., Harris, A.L. Br. J. Cancer (1988) [Pubmed]
  13. The pharmacokinetics of the quinazoline antifolate ICI D 1694 in mice and rats. Jodrell, D.I., Newell, D.R., Gibson, W., Hughes, L.R., Calvert, A.H. Cancer Chemother. Pharmacol. (1991) [Pubmed]
  14. An essential role for water in an enzyme reaction mechanism: the crystal structure of the thymidylate synthase mutant E58Q. Sage, C.R., Rutenber, E.E., Stout, T.J., Stroud, R.M. Biochemistry (1996) [Pubmed]
  15. Crystal structures of a marginally active thymidylate synthase mutant, Arg 126-->Glu. Strop, P., Changchien, L., Maley, F., Montfort, W.R. Protein Sci. (1997) [Pubmed]
  16. Biochemical effects of a quinazoline inhibitor of thymidylate synthetase, N-(4-(N-(( 2-amino-4-hydroxy-6-quinazolinyl)methyl)prop-2-ynylamino) benzoyl)-L-glutamic acid (CB3717), on human lymphoblastoid cells. Jackson, R.C., Jackman, A.L., Calvert, A.H. Biochem. Pharmacol. (1983) [Pubmed]
  17. Formation and retention and biological activity of N10-propargyl-5,8-dideazafolic acid (CB3717) polyglutamates in L1210 cells in vitro. Sikora, E., Jackman, A.L., Newell, D.R., Calvert, A.H. Biochem. Pharmacol. (1988) [Pubmed]
  18. The renal effects of N10-propargyl-5,8-dideazafolic acid (CB3717) and a non-nephrotoxic analogue ICI D1694, in mice. Jodrell, D.I., Newell, D.R., Morgan, S.E., Clinton, S., Bensted, J.P., Hughes, L.R., Calvert, A.H. Br. J. Cancer (1991) [Pubmed]
  19. Inhibition of the growth of human hepatocellular carcinoma in vitro and in athymic mice by a quinazoline inhibitor of thymidylate synthase, CB3717. Curtin, N.J., Harris, A.L., James, O.F., Bassendine, M.F. Br. J. Cancer (1986) [Pubmed]
  20. Pharmacokinetics of the thymidylate synthase inhibitor N10-propargyl-5,8-dideazafolic acid (CB3717) in the mouse. Newell, D.R., Alison, D.L., Calvert, A.H., Harrap, K.R., Jarman, M., Jones, T.R., Manteuffel-Cymborowska, M., O'Connor, P. Cancer treatment reports. (1986) [Pubmed]
  21. Carrier- and receptor-mediated transport of folate antagonists targeting folate-dependent enzymes: correlates of molecular-structure and biological activity. Westerhof, G.R., Schornagel, J.H., Kathmann, I., Jackman, A.L., Rosowsky, A., Forsch, R.A., Hynes, J.B., Boyle, F.T., Peters, G.J., Pinedo, H.M. Mol. Pharmacol. (1995) [Pubmed]
  22. Quinoline antifolate thymidylate synthase inhibitors: variation of the C2- and C4-substituents. Warner, P., Barker, A.J., Jackman, A.L., Burrows, K.D., Roberts, N., Bishop, J.A., O'Connor, B.M., Hughes, L.R. J. Med. Chem. (1992) [Pubmed]
  23. The structural mechanism for half-the-sites reactivity in an enzyme, thymidylate synthase, involves a relay of changes between subunits. Anderson, A.C., O'Neil, R.H., DeLano, W.L., Stroud, R.M. Biochemistry (1999) [Pubmed]
  24. Relationships between resistance to cisplatin and antifolates in sensitive and resistant tumour cell lines. Kelland, L.R., Kimbell, R., Hardcastle, A., Aherne, G.W., Jackman, A.L. Eur. J. Cancer (1995) [Pubmed]
  25. Tomudex (ZD1694): from concept to care, a programme in rational drug discovery. Jackman, A.L., Boyle, F.T., Harrap, K.R. Investigational new drugs. (1996) [Pubmed]
  26. A human leukemia cell line made resistant to two folate analogues, trimetrexate and N10-propargyl-5,8-dideazafolic acid (CB3717). Takemura, Y., Ohnuma, T., Miyachi, H., Sekiguchi, S. J. Cancer Res. Clin. Oncol. (1991) [Pubmed]
  27. Increased thymidylate synthase in L1210 cells possessing acquired resistance to N10-propargyl-5,8-dideazafolic acid (CB3717): development, characterization, and cross-resistance studies. Jackman, A.L., Alison, D.L., Calvert, A.H., Harrap, K.R. Cancer Res. (1986) [Pubmed]
  28. Mechanism of cell death following thymidylate synthase inhibition: 2'-deoxyuridine-5'-triphosphate accumulation, DNA damage, and growth inhibition following exposure to CB3717 and dipyridamole. Curtin, N.J., Harris, A.L., Aherne, G.W. Cancer Res. (1991) [Pubmed]
  29. Induction of remission in hepatocellular carcinoma with a new thymidylate synthase inhibitor, CB3717. A phase II study. Bassendine, M.F., Curtin, N.J., Loose, H., Harris, A.L., James, O.F. J. Hepatol. (1987) [Pubmed]
  30. Serum vitamin B12 levels in patients with primary hepatocellular carcinoma during treatment with CB3717. Buamah, P.K., James, O.F., Skillen, A.W., Harris, A.L. Journal of surgical oncology. (1987) [Pubmed]
 
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