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Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth

Smith, M. C. and Mader, M. M. and Cook, J. A. and Iversen, P. and Ajamie, R. and Perkins, E. and Bloem, L. and Yip, Y. Y. and Barda, D. A. and Waid, P. P. and Zeckner, D. J. and Young, D. A. and Sanchez-Felix, M. and Donoho, G. P. and Wacheck, V. (2016) Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth. Molecular Cancer Therapeutics. ISSN 1535-7163

Abstract

The phosphoinositide-3 kinase (PI3K)/AKT/mammalian target of rapamycin (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 1 and 2 trials for the treatment of human malignancies.

Item Type: Article
Date Deposited: 22 Jul 2016 00:45
Last Modified: 22 Jul 2016 00:45
URI: https://oak.novartis.com/id/eprint/30352

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