PDF - 182 KB, Table S1. Kinase selectivity profile for LY3023414 in Cerep and Life Technologies assays based on a 3-point concentration response curve; Table S2. In vitro inhibitory activity of LY3023414 against kinases in a PC3 cell lysate measured in the KiNativ assay based on a 3-point concentration response curve; Table S3. In vitro cell-based target inhibition in SKOV3, A2780, and AsPC-1; Table S4. Summary of pathway-relevant genetic alterations in cancer cell line panel and in selected patient-derived xenograft tumor models tested; Table S5. Activated caspase-3/7 levels in cell lines treated with 2.5 μM LY3023414 for 48 hours; Table S6. In vitro combination studies with LY3023414 and standard of care agents in various cancer cell lines; Table S7. Time course of in vivo target inhibition in U87 MG xenograft tumors after oral administration of 15 and 30 mg/kg LY3023414; Table S8. Summary of LY3023414 monotherapy efficacy in patient-derived xenograft tumor models; Table S9. Summary of LY3023414 combination efficacy in patient-derived xenograft squamous non-small cell lung cancer (NSCLC) tumor models.
ARTICLE ABSTRACT
The PI3K/AKT/mTOR pathway is among the most frequently altered pathways in cancer cell growth and survival. LY3023414 is a complex fused imidazoquinolinone with high solubility across a wide pH range designed to inhibit class I PI3K isoforms and mTOR kinase. Here, we describe the in vitro and in vivo activity of LY3023414. LY3023414 was highly soluble at pH 2–7. In biochemical testing against approximately 266 kinases, LY3023414 potently and selectively inhibited class I PI3K isoforms, mTORC1/2, and DNA-PK at low nanomolar concentrations. In vitro, inhibition of PI3K/AKT/mTOR signaling by LY3023414 caused G1 cell-cycle arrest and resulted in broad antiproliferative activity in cancer cell panel screens. In vivo, LY3023414 demonstrated high bioavailability and dose-dependent dephosphorylation of PI3K/AKT/mTOR pathway downstream substrates such as AKT, S6K, S6RP, and 4E-BP1 for 4 to 6 hours, reflecting the drug's half-life of 2 hours. Of note, equivalent total daily doses of LY3023414 given either once daily or twice daily inhibited tumor growth to similar extents in multiple xenograft models, indicating that intermittent target inhibition is sufficient for antitumor activity. In combination with standard-of-care drugs, LY3023414 demonstrated additive antitumor activity. The novel, orally bioavailable PI3K/mTOR inhibitor LY3023414 is highly soluble and exhibits potent in vivo efficacy via intermittent target inhibition. It is currently being evaluated in phase I and II trials for the treatment of human malignancies. Mol Cancer Ther; 15(10); 2344–56. ©2016 AACR.
