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IC50: 64.9, 42.1, 10.6, and 19.1 nM for Akt1(pT308), Akt1 (pS473), P70S6(pT389), and S6RP(pS240/242), respectively.

LY3023414 is an ATP competitive inhibitor of the class I PI3K isoforms, mTOR and DNA-PK.

The phosphoinositide-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is one of the most frequently altered pathways in cancer cell growth and survival.

In vitro: In biochemical testing against approximately 266 kinases, LY3023414 was found to potently and selectively inhibit class I PI3K isoforms, mTORC1/2, as well as DNA-PK at low concentrations. In addition, inhibition of PI3K/AKT/mTOR signaling by LY3023414 led to G1 cell-cycle arrest and resulted in broad antiproliferative activity in cancer cell panel [1].

In vivo: LY3023414 showed high bioavailability and dose-dependent dephosphorylation of PI3K/AKT/mTOR pathway downstream substrates for 4 to 6 hours, indicating LY3023414's half-life of 2 hours. Moreover, equivalent total daily doses of LY3023414 given either once or twice daily could inhibit tumor growth to the similar extents in multiple xenograft models, demonstrating intermittent target inhibition was sufficient for antitumor activity [1].

Clinical trial: LY3023414 appears to be safe when administered as single agent up to 325 mg QD or 200 mg BID. Currently, LY3023414 is investigated in tumor-specific expansion cohorts for breast cancer, mesothelioma, Non-Hodgkin Lymphoma as well as NSCLC (Clinical trial information: NCT01655225).

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