LY2584702 tosylate

LY2584702 Tosylate is a selective, ATP-competitive p70S6K inhibitor with IC50 of 4 nM. Phase 1. (In Vitro) :LY-2584702 (LY2584702) inhibits phosphorylation of the S6 ribosomal protein (pS6) in HCT116 colon cancer cells with an IC50 of 0.1-0.24 μM. In S6K1 enzyme assay, the IC50 of LY-2584702 (LY2584702) is 2 nM. For pS6 inhibition in cells, the IC50=100 nM. LY-2584702 has some activity against the S6K-related kinases MSK2 and RSK at high concentrations (enzyme assay IC50=58-176 nM) . LY-2584702 inhibits S6K activity in EOMA cells, as determined by the phosphorylation of its downstream effector S6, in a dose-dependent manner. Proliferation of A549 is significantly inhibited by LY-2584702 (LY2584702) treating over 24 h at 0.1 μM (P<0.05) ; and the trend of decline is more conspicuous with longer treatment and/or with the increased drug concentration (all P<0.05) . Similar results are also observed in SK-MES-1, although the obvious inhibition is led by LY-2584702 at 0.6 μM (P<0.05), much higher than that of A549. (In Vivo) :LY-2584702 demonstrates significant single-agent efficacy in both U87MG glioblastoma and HCT116 colon carcinoma xenograft models at two dose levels of 2.5 mg/kg twice daily (BID) and 12.5 mg/kg BID. LY-2584702 demonstrates statistically significant tumour growth reduction at TMED50 (threshold minimum effective dose 50%) (2.3 mg/kg) and TMED90 (10 mg/kg) in the HCT116 colon carcinoma xenograft model. To examine the role of S6K in vivo, EOMA cells expressing shAkt3 are implanted in nu/nu mice, then treated for 14 days with LY-2584702 or Rapamycin. Analysis of tumors removed after 14 days shows that LY-2584702 inhibits S6 phosphorylation almost as effectively as Rapamycin. Loss of Akt3 increases tumor growth as compared with pLKO. LY-2584702 treatment alone does not significantly affect the growth of pLKO tumors. However, LY-2584702 significantly reduces the growth of tumors with shAkt3.