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In Vivo Pharmacokinetic Features, Toxicity Profile, and Chemosensitizing Activity of -Cyano-ß-hydroxy-ß- methyl-N-(2,5-dibromophenyl)propenamide (LFM-A13), a Novel Antileukemic Agent Targeting Bruton’s Tyrosine Kinase

Parker Hughes Cancer Center [F. M. U., M. C-C., A. V., C-L. C.], Departments of Pharmaceutical Sciences [H. C., C-L. C.], Chemistry [Y. Z.], Experimental Oncology [M.C-C., A. V., E. L.], and Pathology [B. W., R. C.], and the Drug Discovery Program [F. M. U.], Parker Hughes Institute, St. Paul, Minnesota 55113

The purpose of the present study was to examine the in vivo pharmacokinetics and activity of -cyano-ß-hydroxy-ß-methyl-N-(2,5-dibromophenyl)propenamide (LFM-A13), a novel antileukemic agent targeting Bruton’s tyrosine kinase (BTK). We have applied an analytical high-performance liquid chromatography method for the quantitative detection of LFM-A13 in plasma samples. Our findings indicate that LFM-A13 is quickly absorbed, with the time required to reach the maximum plasma drug concentration (t_max) being 10–18 min after i.p. administration with nearly complete bioavailability. LFM-A13 had an elimination half-life of 17–32 min after i.p. administration at dose levels of 10–50 mg/kg. LFM-A13 exhibited a dose-dependent and significant increase in the values of normalized area under the curve and maximum concentration (C_max) as well as a dose-dependent and significant decrease in clearance values, suggesting a saturable clearance mechanism. LFM-A13 was not toxic to mice when administered systemically at dose levels ranging from 10 to 80 mg/kg. Highly effective BTK-inhibitory and apoptosis-promoting plasma concentrations of LFM-A13 could be achieved in mice without toxicity. LFM-A13 exhibited a favorable pharmacokinetic behavior that was not adversely affected by the standard chemotherapy drugs vincristine, methylprednisolone, or L-asparaginase (when used as combination treatment, VPL) and significantly improved the chemotherapy response and survival outcome of mice challenged with BCL-1 leukemia cells. Whereas only 14% of mice treated with the standard triple-drug combination VPL became long-term survivors, 41% of mice treated with this combination plus LFM-A13 survived long-term. LFM-A13 prolonged the median survival time of VPL-treated mice from 37 to 58 days. Our results confirm and extend previous studies regarding the role of BTK chemotherapy resistance of B-lineage leukemic cells (S. Mahajan et al., J. Biol. Chem., 274: 9587–9599, 1999). BTK inhibitors such as LFM-A13 may be useful as a new class of chemosensitizing and apoptosis-promoting antileukemic agents for treatment of patients with chemotherapy-resistant B-lineage leukemias or lymphomas.

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