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Chemical Compound Review

CHEMBL279433     4-[[5-[[4-(3-chlorophenyl)-3- oxo-piperazin...

Synonyms: AG-K-24107, SureCN1683541, CHEBI:129948, CTK7C7787, DNC003581, ...
 
 
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Disease relevance of L-778,123

 

High impact information on L-778,123

  • In fact, L-778,123 is more effective in inhibiting primary lung progression in mice with a p53 mutation and/or an Ink4a/Arf deletion than in wild-type animals [6].
  • Next, we examined the chemopreventive efficacy of a new FTI, L-778,123, on lung tumor development in A/J mice and transgenic mice with a dominant-negative p53 mutation and/or heterozygous deletion of Ink4a/Arf [6].
  • Treatment of mice with L-778,123 for a period of 10 weeks from 20 weeks to 30 weeks post carcinogen initiation resulted in an approximately 50% decrease in tumor multiplicity in wild-type mice and mice with a dominant-negative p53 mutation and/or heterozygous deletion of the Ink4a/Arf tumor suppressor genes [6].
  • Both reversible inhibition of HDJ2 farnesylation and radiosensitization of a study patient-derived cell line were demonstrated in the presence of L-778,123 [2].
  • A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer [2].
 

Biological context of L-778,123

  • This study also sought to characterize the pharmacological behavior of L-778,123 and to determine whether the desired biological effect, inhibition of protein farnesylation, could be detected and assessed during treatment [1].
  • Pharmacokinetics were linear, and L-778,123 plasma concentrations at steady-state (mean, 8.09 +/- 3.11 microM at 560 mg/m(2)/day) exceeded IC(50) values (range, 0.07-5.35 microM) required for growth inhibition and cytotoxicity in preclinical studies [1].
  • Although FTase and GGTase-I have very similar active sites, L-778,123 adopts different binding modes in the two enzymes; in FTase, L-778,123 is competitive with the protein substrate, whereas in GGTase-I, L-778,123 is competitive with the lipid substrate and inhibitor binding is synergized by tetrahedral anions [7].
  • PBMC proliferation was inhibited by L-778,123 with an IC50 of 0.92 +/- 0.23 microM, and addition of CsA did not increase the potency [4].
  • The ability of L-778,123 to inhibit IL-2 receptor signaling was investigated by measuring IL-2 induced proliferation in CTLL-2 cells and IL-2 prevention of apoptosis in activated human PBMC [4].
 

Anatomical context of L-778,123

 

Associations of L-778,123 with other chemical compounds

  • R115777 and L-778,123 were well tolerated in these studies but showed no significant activity as single-agent therapy in relapsed SCLC or untreated NSLC [9].
 

Gene context of L-778,123

  • Crystallographic analysis reveals that anticancer clinical candidate L-778,123 inhibits protein farnesyltransferase and geranylgeranyltransferase-I by different binding modes [7].
  • L-778,123 abrogated IL-2 induced proliferation of CTLL-2 cells with an IC50 of 0.81 +/- 0.44 microM [4].
  • L-778,123 did not inhibit IL-2 and IFN-gamma production by T cells [4].
  • L-778,123 inhibited HDJ2 prenylation for the duration of the drug infusion in a dose-dependent manner, but seemed to plateau above 560 mg/m(2)/day [1].
  • L-778,123 inhibited lectin induced expression of CD71 and CD25 with IC50's of 6.48 +/- 1.31 microM and 84.1 +/- 50.0 microM, respectively [4].
 

Analytical, diagnostic and therapeutic context of L-778,123

References

  1. A phase I and pharmacological study of the farnesyl protein transferase inhibitor L-778,123 in patients with solid malignancies. Britten, C.D., Rowinsky, E.K., Soignet, S., Patnaik, A., Yao, S.L., Deutsch, P., Lee, Y., Lobell, R.B., Mazina, K.E., McCreery, H., Pezzuli, S., Spriggs, D. Clin. Cancer Res. (2001) [Pubmed]
  2. A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer. Martin, N.E., Brunner, T.B., Kiel, K.D., DeLaney, T.F., Regine, W.F., Mohiuddin, M., Rosato, E.F., Haller, D.G., Stevenson, J.P., Smith, D., Pramanik, B., Tepper, J., Tanaka, W.K., Morrison, B., Deutsch, P., Gupta, A.K., Muschel, R.J., McKenna, W.G., Bernhard, E.J., Hahn, S.M. Clin. Cancer Res. (2004) [Pubmed]
  3. A Phase I trial of the farnesyltransferase inhibitor L-778,123 and radiotherapy for locally advanced lung and head and neck cancer. Hahn, S.M., Bernhard, E.J., Regine, W., Mohiuddin, M., Haller, D.G., Stevenson, J.P., Smith, D., Pramanik, B., Tepper, J., DeLaney, T.F., Kiel, K.D., Morrison, B., Deutsch, P., Muschel, R.J., McKenna, W.G. Clin. Cancer Res. (2002) [Pubmed]
  4. Inhibition of lymphocyte activation and function by the prenylation inhibitor L-778,123. Si, M.S., Reitz, B.A., Borie, D.C. Investigational new drugs. (2005) [Pubmed]
  5. Farnesyl transferase inhibitors: a major breakthrough in anticancer therapy? Naples, 12 April 2002. Caponigro, F. Anticancer Drugs (2002) [Pubmed]
  6. Farnesyltransferase inhibitors are potent lung cancer chemopreventive agents in A/J mice with a dominant-negative p53 and/or heterozygous deletion of Ink4a/Arf. Zhang, Z., Wang, Y., Lantry, L.E., Kastens, E., Liu, G., Hamilton, A.D., Sebti, S.M., Lubet, R.A., You, M. Oncogene (2003) [Pubmed]
  7. Crystallographic analysis reveals that anticancer clinical candidate L-778,123 inhibits protein farnesyltransferase and geranylgeranyltransferase-I by different binding modes. Reid, T.S., Long, S.B., Beese, L.S. Biochemistry (2004) [Pubmed]
  8. The effects of the farnesyl transferase inhibitor FTI L-778,123 on normal, myelodysplastic, and myeloid leukemia bone marrow progenitor proliferation in vitro. Huang, X.K., Meyer, P., Li, B., Raza, A., Preisler, H.D. Leuk. Lymphoma (2003) [Pubmed]
  9. Farnesyl transferase inhibitors for patients with lung cancer. Johnson, B.E., Heymach, J.V. Clin. Cancer Res. (2004) [Pubmed]
  10. High-performance liquid chromatography/mass spectrometry characterization of Ki4B-Ras in PSN-1 cells treated with the prenyltransferase inhibitor L-778,123. Buser, C.A., Dinsmore, C.J., Fernandes, C., Greenberg, I., Hamilton, K., Mosser, S.D., Walsh, E.S., Williams, T.M., Koblan, K.S. Anal. Biochem. (2001) [Pubmed]
  11. American Association for Cancer Research 1999: 10-14 April, Philadelphia, Pennsylvania. Lavelle, F. Expert opinion on investigational drugs. (1999) [Pubmed]
 
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