Supplementary Figures S1-S6 from Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth

Smith, Michele C.; Mader, Mary M.; Cook, James A.; Iversen, Philip; Ajamie, Rose; Perkins, Everett; Bloem, Laura; Yip, Yvonne Y.; Barda, David A.; Waid, Philip P.; Zeckner, Douglas J.; Young, Debra A.; Sanchez-Felix, Manuel; Donoho, Gregory P.; Wacheck, Volker

doi:10.1158/1535-7163.22503379.v1

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Supplementary Figures S1-S6 from Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth

journal contribution

posted on 2023-04-03, 14:42 authored by Michele C. Smith, Mary M. Mader, James A. Cook, Philip Iversen, Rose Ajamie, Everett Perkins, Laura Bloem, Yvonne Y. Yip, David A. Barda, Philip P. Waid, Douglas J. Zeckner, Debra A. Young, Manuel Sanchez-Felix, Gregory P. Donoho, Volker Wacheck

PDF - 564 KB, Figure S1. Duodenal compound concentration profile of multiple compounds from a gastroduodenal passage simulation model; Figure S2. Kinetics of LY3023414 inhibition of PI3Kα; Figure S3. LY3023414 inhibition of mTORC1 in a concentration-dependent manner after ex vivo treatment of PMBC or whole blood; Figure S4. Activity of LY3023414 in a tumor clonogenic assay with a panel of patient-derived tumor xenografts passaged in nude mice and then grown in soft agar; Figure S5. Mean (±SD) concentrations of LY3023414 in male mice plasma, male rat plasma, and male beagle dog plasma following single dose; Figure S6. In vivo efficacy of LY3023414 and rapamycin alone and in combination using (A) H1975 and (B) 786-O xenograft tumor models.

Funding

Eli Lilly and Company

History

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.