LY3023414

LY3023414 is a potent, dual PI3K/mTOR inhibitor with IC50 of 6.07 nM, 77.6 nM, 38 nM, 23.8 nM, 165 nM and 4.24 nM for PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ, mTOR and DNA-PK, respectively; inhibits the phosphorylation of AKT at position T308 with IC50 of 106 nM in the PTEN-deficient U87 MG glioblastoma cell line, 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) ; causes G1 cell-cycle arrest and shows broad antiproliferative activity in cancer cell panel screens; exhibits antitumor activity in multiple xenograft models.Lung Cancer Phase 2 Clinical (In Vitro) :In cell-based assays, Samotolisib (LY3023414) inhibition of PI3K and mTOR is assessed in the PTEN-deficient U87 MG glioblastoma cell line. Samotolisib inhibits the phosphorylation of Akt at position T308 downstream of PI3K at an IC50 of 106 nM. Similarly, Samotolisib 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 Samotolisib. Similar IC50 concentrations for PI3K and mTOR phosphorylation targets are observed in other cell lines with activated PI3K/Akt/mTOR pathways. The ability of Samotolisib to inhibit cancer cell proliferation is evaluated in 32 human cancer cell lines from different tumor types in culture after Samotolisib treatment for 2 to 3 cell doublings in dose–response studies. Samotolisib demonstrates potent single-agent activity and IC50 values below 122 nM in half of the cell lines tested. (In Vivo) :The ability of Samotolisib (LY3023414) to inhibit tumor growth is studied in several xenograft models exhibiting mutations or deletions that activate the PI3K/Akt/mTOR pathway. Treatment with Samotolisib 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 Samotolisib 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.