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Developing a novel dual PI3K–mTOR inhibitor from the prodrug of a metabolite
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. Af...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove Medical Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659256/ https://www.ncbi.nlm.nih.gov/pubmed/29118584 http://dx.doi.org/10.2147/OTT.S142492 |
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author | Zhou, Yan Zhang, Genyan Wang, Feng Wang, Jin Ding, Yanwei Li, Xinyu Shi, Chongtie Li, Jiakui Shih, Chengkon You, Song |
author_facet | Zhou, Yan Zhang, Genyan Wang, Feng Wang, Jin Ding, Yanwei Li, Xinyu Shi, Chongtie Li, Jiakui Shih, Chengkon You, Song |
author_sort | Zhou, Yan |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5659256 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Dove Medical Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-56592562017-11-08 Developing a novel dual PI3K–mTOR inhibitor from the prodrug of a metabolite Zhou, Yan Zhang, Genyan Wang, Feng Wang, Jin Ding, Yanwei Li, Xinyu Shi, Chongtie Li, Jiakui Shih, Chengkon You, Song Onco Targets Ther Original Research 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. Dove Medical Press 2017-10-20 /pmc/articles/PMC5659256/ /pubmed/29118584 http://dx.doi.org/10.2147/OTT.S142492 Text en © 2017 Zhou et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. |
spellingShingle | Original Research Zhou, Yan Zhang, Genyan Wang, Feng Wang, Jin Ding, Yanwei Li, Xinyu Shi, Chongtie Li, Jiakui Shih, Chengkon You, Song Developing a novel dual PI3K–mTOR inhibitor from the prodrug of a metabolite |
title | Developing a novel dual PI3K–mTOR inhibitor from the prodrug of a metabolite |
title_full | Developing a novel dual PI3K–mTOR inhibitor from the prodrug of a metabolite |
title_fullStr | Developing a novel dual PI3K–mTOR inhibitor from the prodrug of a metabolite |
title_full_unstemmed | Developing a novel dual PI3K–mTOR inhibitor from the prodrug of a metabolite |
title_short | Developing a novel dual PI3K–mTOR inhibitor from the prodrug of a metabolite |
title_sort | developing a novel dual pi3k–mtor inhibitor from the prodrug of a metabolite |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659256/ https://www.ncbi.nlm.nih.gov/pubmed/29118584 http://dx.doi.org/10.2147/OTT.S142492 |
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