XK469, 2-[4-(7-chloro-2-quinoxalinyloxy)phenoxy]propionic acid, is among the most broadly active antitumor agents that have been evaluated in our laboratories. The agent is currently in development in a collaborative effort between the National Cancer Institute, the DuPont Corporation and our laboratories with expectations for clinical trial to begin in 2000. The objectives of the project are to elicit incisive information on the mechanism of action of XK469 and to improve the therapeutic index of the lead agent through (1) a comprehensive synthetic program of congeners and bioisosters of XK469 to (a) identify the active centers of the lead compound, i.e., the pharmacophore, which is responsible for the high solid tumor selectivity exhibited by this agent and (b) to improve such limitations as toxicity and host recovery times, among others observed in the evaluation of XK469 in mice; (2) an evaluation of all newly synthesized analogs in an in vitro, disk-diffusion-soft agar-colony-formation-assay to determine the cytotoxicity of each agent against leukemias, solid tumors and normal cells. Analogs that exhibit solid tumor selectivity will be evaluated in tumor-bearing mice for in vivo efficacy. Analogs demonstrating high activity will then be evaluated in mice carrying a variety of tumors of both mouse and human origin, utilizing, in addition, SCID mice for human tumors.; (3) corroboration, through synthesis, of structures assigned by mass spectrometry to mouse-urinary metabolites of XK469; (4) the use of structure-activity data to establish quantitative structure activity relationships, using the methodology of comparative molecular field analysis (CoMFA) as the basis for the design of novel compounds of predicted high activity; (5) an investigative exploration of the modes of cytotoxic action of XK469 and its analogs; and (6) determine the effect of XK469 on selected molecular targets.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA082341-05
Application #
6696361
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Lees, Robert G
Project Start
2000-02-15
Project End
2005-07-31
Budget Start
2004-02-01
Budget End
2005-07-31
Support Year
5
Fiscal Year
2004
Total Cost
$224,091
Indirect Cost
Name
Wayne State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Kessel, David; Reiners Jr, John J; Hazeldine, Stuart T et al. (2007) The role of autophagy in the death of L1210 leukemia cells initiated by the new antitumor agents, XK469 and SH80. Mol Cancer Ther 6:370-9
Kessel, David; Vicente, M Graca H; Reiners Jr, John J (2006) Initiation of apoptosis and autophagy by photodynamic therapy. Lasers Surg Med 38:482-8
Hazeldine, Stuart T; Polin, Lisa; Kushner, Juiwanna et al. (2006) Synthesis and biological evaluation of conformationally constrained analogs of the antitumor agents XK469 and SH80. Part 5. Bioorg Med Chem 14:2462-7
Hazeldine, Stuart T; Polin, Lisa; Kushner, Juiwanna et al. (2005) Part 3: synthesis and biological evaluation of some analogs of the antitumor agents, 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid, and 2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}propionic acid. Bioorg Med Chem 13:1069-81
Hazeldine, Stuart T; Polin, Lisa; Kushner, Juiwanna et al. (2005) Synthetic modification of the 2-oxypropionic acid moiety in 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid (XK469), and consequent antitumor effects. Part 4. Bioorg Med Chem 13:3910-20
Hazeldine, Stuart T; Polin, Lisa; Kushner, Juiwanna et al. (2002) II. Synthesis and biological evaluation of some bioisosteres and congeners of the antitumor agent, 2-(4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy)propionic acid (XK469). J Med Chem 45:3130-7
Polin, Lisa; White, Kathryn; Kushner, Juiwanna et al. (2002) Preclinical efficacy evaluations of XK-469: dose schedule, route and cross-resistance behavior in tumor bearing mice. Invest New Drugs 20:13-22
Poondru, Srinivasu; Parchment, Ralph E; Purohit, Vivek et al. (2002) Lack of in vitro-in vivo correlation of a novel investigational anticancer agent, SH 30. Invest New Drugs 20:23-33
Kessel, D; Horwitz, J P (2001) Pro-apoptotic interactions between XK469 and the peripheral benzodiazepine receptor. Cancer Lett 168:141-4
Hazeldine, S T; Polin, L; Kushner, J et al. (2001) Design, synthesis, and biological evaluation of analogues of the antitumor agent, 2-(4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy)propionic acid (XK469). J Med Chem 44:1758-76