Biological Activity
LY3023414 potently and selectively inhibits class I PI3K isoforms, DNA-PK, and mTORC1/2 with IC50s of 6.07 nM, 77.6 nM, 38 nM, 23.8 nM, 4.24 nM and 165 nM for PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ, DNA-PK and mTOR, respectively. LY3023414 potently inhibits mTORC1/2 at low nanomolar concentrations.
In Vitro
In cell-based assays, LY3023414 inhibition of PI3K and mTOR is assessed in the PTEN-deficient U87 MG glioblastoma cell line. LY3023414 inhibits the phosphorylation of Akt at position T308 downstream of PI3K at an IC50 of 106 nM. Similarly, LY3023414 inhibits phosphorylation of Akt at position S473 (IC50=94.2 nM) by mTORC2 as well as phosphorylation of mTORC1 kinase targets p70S6K (position T389; IC50=10.6 nM) and 4E-BP1 (positions T37/46; IC50=187 nM). The downstream phosphorylation of S6RP at positions pS240/244 (IC50=19.1 nM) by p70S6K is inhibited as well, indicating target inhibition along the entire PI3K/Akt/mTOR pathway by LY3023414. Similar IC50 concentrations for PI3K and mTOR phosphorylation targets are observed in other cell lines with activated PI3K/Akt/mTOR pathways. The ability of LY3023414 to inhibit cancer cell proliferation is evaluated in 32 human cancer cell lines from different tumor types in culture after LY3023414 treatment for 2 to 3 cell doublings in dose–response studies. LY3023414 demonstrates potent single-agent activity and IC50 values below 122 nM in half of the cell lines tested[1].
In Vivo
The ability of LY3023414 to inhibit tumor growth is studied in several xenograft models exhibiting mutations or deletions that activate the PI3K/Akt/mTOR pathway. Treatment with LY3023414 at 3, 6, or 10 mg/kg twice daily orally for 28 days results in dose-responsive inhibition of tumor growth in the PTEN-deleted U87 MG xenograft model. This treatment produces similar TGI in models exhibiting PTEN truncation (786-O), activating PI3Kα mutation (NCI-H1975), and transgenic Eμ-myc mutant PI3Kα-driven leukemia models. Of note, the total daily dose of LY3023414 appears to result in equipotent antitumor activity: 12 mg/kg once daily and 6 mg/kg twice daily produces similar delta T/C values (42% and 38%, respectively) in U87 MG[1].
References & source
Published experimental findings depend on the model and assay conditions. They do not guarantee equivalent performance in every application. For laboratory research use only.
