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A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery

mTOR/MEK bifunctional inhibitors have the potential to surmount the drug resistance aroused from cross talk between PI3K/Akt/mTOR (PAM) and Ras/MEK/ERK pathways. Herein, we report the discovery of a conjugated dual-targeted molecule, compound 13, as the prototype mTOR/MEK bifunctional inhibitor. It...

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Autores principales: Tao, Qiangqiang, Fang, Fang, Li, Jiaming, Wang, Yong, Zhao, Can, Liang, Jingtai, Ma, Xiaodong, Wang, Hao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223898/
https://www.ncbi.nlm.nih.gov/pubmed/32435126
http://dx.doi.org/10.1007/s00044-020-02502-x
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author Tao, Qiangqiang
Fang, Fang
Li, Jiaming
Wang, Yong
Zhao, Can
Liang, Jingtai
Ma, Xiaodong
Wang, Hao
author_facet Tao, Qiangqiang
Fang, Fang
Li, Jiaming
Wang, Yong
Zhao, Can
Liang, Jingtai
Ma, Xiaodong
Wang, Hao
author_sort Tao, Qiangqiang
collection PubMed
description mTOR/MEK bifunctional inhibitors have the potential to surmount the drug resistance aroused from cross talk between PI3K/Akt/mTOR (PAM) and Ras/MEK/ERK pathways. Herein, we report the discovery of a conjugated dual-targeted molecule, compound 13, as the prototype mTOR/MEK bifunctional inhibitor. It exhibited moderately high inhibitory activity against mTOR and MEK1 with IC(50) values of 0.19 μM and 0.98 μM, respectively. In particular, it displayed attractive antiproliferative activity against both A549 (GI(50) = 4.66 μM) and HCT116 (GI(50) = 5.47 μM) cell lines. To our knowledge, it has been the first example of a conjugated mTOR/MEK bifunctional inhibitor. In addition, from this proof-of-principle study, it has become evident that the single-agent dual inhibition of mTOR and MEK can be fulfilled via covalently attaching mTOR kinase inhibitor to an allosteric MEK inhibitor.
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spelling pubmed-72238982020-05-15 A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery Tao, Qiangqiang Fang, Fang Li, Jiaming Wang, Yong Zhao, Can Liang, Jingtai Ma, Xiaodong Wang, Hao Med Chem Res Original Research mTOR/MEK bifunctional inhibitors have the potential to surmount the drug resistance aroused from cross talk between PI3K/Akt/mTOR (PAM) and Ras/MEK/ERK pathways. Herein, we report the discovery of a conjugated dual-targeted molecule, compound 13, as the prototype mTOR/MEK bifunctional inhibitor. It exhibited moderately high inhibitory activity against mTOR and MEK1 with IC(50) values of 0.19 μM and 0.98 μM, respectively. In particular, it displayed attractive antiproliferative activity against both A549 (GI(50) = 4.66 μM) and HCT116 (GI(50) = 5.47 μM) cell lines. To our knowledge, it has been the first example of a conjugated mTOR/MEK bifunctional inhibitor. In addition, from this proof-of-principle study, it has become evident that the single-agent dual inhibition of mTOR and MEK can be fulfilled via covalently attaching mTOR kinase inhibitor to an allosteric MEK inhibitor. Springer US 2020-01-13 2020 /pmc/articles/PMC7223898/ /pubmed/32435126 http://dx.doi.org/10.1007/s00044-020-02502-x Text en © Springer Science+Business Media, LLC, part of Springer Nature 2020 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
spellingShingle Original Research
Tao, Qiangqiang
Fang, Fang
Li, Jiaming
Wang, Yong
Zhao, Can
Liang, Jingtai
Ma, Xiaodong
Wang, Hao
A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery
title A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery
title_full A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery
title_fullStr A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery
title_full_unstemmed A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery
title_short A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery
title_sort conjugated mtor/mek bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223898/
https://www.ncbi.nlm.nih.gov/pubmed/32435126
http://dx.doi.org/10.1007/s00044-020-02502-x
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