TAK-733

TAK-733 (TAK733, TAK 733) is a potent, selective, allosteric inhibitor of MEK with IC50 of 3.2 nM (MEK1) ; shows selectivity for MEK1 over a panel of 18 kinases, receptors, and ion channels at uM; inhibits ERK phosphorylation in vitro with EC50 of 1.9 nM, also inhibits proliferation of A375 and COLO 205 cells with IC50 of 3.1 nM and 2.1 nM, respectively; as well as 14 cutaneous melanoma cell lines (IC50s=0.1 μM in vitro. Thirty-four melanoma cell lines are exposed in vitro to increasing concentrations of TAK-733 for 72 hours. Of the 34 cell lines, 27 are BRAFV600E mutant and 7 are wild-type. SRB proliferation assays are performed and the resulting IC50 concentrations allowed stratification of cell lines into three categories: relatively resistant, intermediate, and highly sensitive. Relatively resistant and highly sensitive lines are assigned based on an IC50 that differ by at least 10 fold. (In Vivo) :The pharmacokinetics of TAK-733 is evaluated in nude mouse, rat, dog and monkey. Low clearance and high oral bioavailability are observed in all species. TAK-733 demonstrates broad antitumor activity in mouse xenograft models of human cancer including models of melanoma, colorectal, NSCLC, pancreatic and breast cancer. Daily oral administration of 1, 3, 10, and 30 mg/kg of TAK-733 for 14 days (Days 10 to 23) results in tumor growth delay in the A375 cell-implanted mice (5/group) . TAK-733 (35, 70, 100, and 160 mg/kg) also significantly inhibits tumor growth on an intermittent dosing schedule of 3 days per week for 2 weeks (Days 10, 13, 15, 17, 20, and 22) . Three partial regressions (PR), a 60% response rate, are observed in mice administered with 30 mg/kg of TAK-733 daily and in mice administered with 160 mg/kg of TAK-733 intermittently. Responses, CR (complete regression) and partial regressions (PR) are also observed in mice administered with 70, 100, and 160 mg/kg of TAK-733 intermittently. The tumor regression rate is more pronounced with the intermittent administration regimen; the greatest reduction in tumor volume is observed at 160 mg/kg (57.29%), versus a maximum reduction of 46.97% at 30 mg/kg once daily. By the last day of administration, tumor growth is significantly (p<0.05 for %T/C, Student's t-test) inhibited in mice administered 3, 10, and 30 mg/kg once daily or 35, 70, 100, and 160 mg/kg intermittently.