LY3023414

1386874-06-1

C23H26N4O3

DMSO : 50 mg/mL (123.01 mM; Need ultrasonic)

PI3K/Akt/mTOR; Cell Cycle/DNA Damage; PI3K/Akt/mTOR; PI3K/Akt/mTOR; Autophagy

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 PI3Kalpha, PI3Kbeta, PI3Kdelta, PI3Kgamma, DNA-PK and mTOR, respectively. LY3023414 potently inhibits mTORC1/2 at low nanomolar concentrations. IC50 & Target: IC50: 6.07+/-3.38 nM (PI3Kalpha), 77.6+/-40.1 nM (PI3Kbeta), 38 nM (PI3Kdelta), 23.8 nM (PI3Kgamma), 165+/-92.5 nM (mTOR), 4.24 nM (DNA-PK)^[2]
mTORC1/2^[2] 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 PI3Kalpha mutation (NCI-H1975), and transgenic Eu-myc mutant PI3Kalpha-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].