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Developing a novel dual PI3K–mTOR inhibitor from the prodrug of a metabolite

Authors Zhou Y, Zhang GY, Wang F, Wang J, Ding YW, Li XY, Shi CT, Li JK, Shih CK, You S

Received 24 May 2017

Accepted for publication 23 August 2017

Published 20 October 2017 Volume 2017:10 Pages 5077—5087


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Dr Carlos E Vigil

Yan Zhou,1,2 Genyan Zhang,2 Feng Wang,2 Jin Wang,2 Yanwei Ding,2 Xinyu Li,2 Chongtie Shi,2 Jiakui Li,2 Chengkon Shih,2 Song You1

1The School of Life Science and Biopharmaceutical, Shenyang Pharmaceutical University, Shenyang, 2Department of Project Management, Medicinal Chemistry, Pharmacology, Drug Metabolism, and Pharmacokinetics, Toxicology, Xuanzhu Pharma, Jinan, China

Abstract: This study presents a process of developing a novel PI3K–mTOR inhibitor through the prodrug of a metabolite. The lead compound (compound 1) was identified with similar efficacy as that of NVP-BEZ235 in a tumor xenograft model, but the exposure of compound 1 was much lower than that of NVP-BEZ235. After reanalysis of the blood sample, a major metabolite (compound 2) was identified. Compound 2 exerted similar in vitro activity as compound 1, which indicated that compound 2 was an active metabolite and that the in vivo efficacy in the animal model came from compound 2 instead of compound 1. However, compound 1 was metabolized into compound 2 predominantly in the liver microsomes of mouse, but not in the liver microsomes of rat, dog, or human. In order to translate the efficacy in the animal model into clinical development or predict the pharmacokinetic/pharmacodynamic parameters in the clinical study using a preclinical model, we developed the metabolite (compound 2) instead of compound 1. Due to the low bioavailability of compound 2, its prodrug (compound 3) was designed and synthesized to improve the solubility. The prodrug was quickly converted to compound 2 through both intravenous and oral administrations. Because the prodrug (compound 3) did not improve the oral exposure of compound 2, developing compound 3 as an intravenous drug was considered by our team, and the latest results will be reported in the future.

Keywords: PI3K, mTOR, NVP-BEZ235, prodrug, metabolite, antitumor

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