LY2857785 exhibits high specificity against a panel of 114 protein kinases, inhibiting only 5 others with an IC50 under 0.1 μM, and a total of 14 kinases below 1 μM. At the cellular level, in U2OS cells, it blocks CTD P-Ser2 and CTD P-Ser5 with IC50s of 0.089 (n=13) and 0.042 (n=1) μM, respectively. Yet, LY2857785 only slightly increases G2-M DNA content from 35% to 55%, with an EC50 of 0.135 μM. The compound demonstrates strong, exposure- and time-dependent inhibition of cell proliferation in MV-4-11, RPMI8226, and L363 cell lines. With 4 to 24 hours of incubation, maximal inhibition occurs at 8 hours, with IC50 values of 0.04, 0.2, and 0.5 μM for MV-4-11, RPMI8226, and L363 cells, respectively. LY2857785 also induces time-dependent apoptosis in cancer cells, reaching peak effectiveness at 8 hours with an IC50 of 0.5 μM in L363 cells[1].
体内研究
In mice with HCT116 xenograft tumors, LY2857785 potently inhibits RNAP II CTD P-Ser2 in a dose-dependent manner, with TED50 of 4.4 mg/kg and TEC50 of 0.36 μM. The compound maintains significant CTD P-Ser2 inhibition for 3 to 6 hours at TED70 (8 mg/kg) in both HCT116 and MV-4-11 nude mice xenograft models. In the MV-4-11 xenograft model in nude rats, LY2857785 similarly exhibits dose-dependent CTD P-Ser2 inhibition lasting 8 hours at TED70 (7 mg/kg) and TED90 (10 mg/kg). LY2857785 shows pronounced tumor reduction in the AML MV-4-11 xenograft model, using either i.v. bolus in mice or i.v. infusion in rats[1].
体外研究
LY2857785 exhibits high specificity against a panel of 114 protein kinases, inhibiting only 5 others with an IC50 under 0.1 μM, and a total of 14 kinases below 1 μM. At the cellular level, in U2OS cells, it blocks CTD P-Ser2 and CTD P-Ser5 with IC50s of 0.089 (n=13) and 0.042 (n=1) μM, respectively. Yet, LY2857785 only slightly increases G2-M DNA content from 35% to 55%, with an EC50 of 0.135 μM. The compound demonstrates strong, exposure- and time-dependent inhibition of cell proliferation in MV-4-11, RPMI8226, and L363 cell lines. With 4 to 24 hours of incubation, maximal inhibition occurs at 8 hours, with IC50 values of 0.04, 0.2, and 0.5 μM for MV-4-11, RPMI8226, and L363 cells, respectively. LY2857785 also induces time-dependent apoptosis in cancer cells, reaching peak effectiveness at 8 hours with an IC50 of 0.5 μM in L363 cells[1].
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