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Design, synthesis and biological evaluation of erlotinib-based IDO1 inhibitors
Erlotinib is a highly specific and reversible epidermal growth factor receptor tyrosine kinase inhibitor for the targeted therapy of non-small-cell lung cancer (NSCLC) However, the efficacy of erlotinib is limited because the development of drug resistance during chemotherapy. Indoleamine 2,3-dioxyg...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9399373/ https://www.ncbi.nlm.nih.gov/pubmed/36034879 http://dx.doi.org/10.3389/fphar.2022.940704 |
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author | Hou, Xi-xi Gong, Xiao-qing Mao, Long-fei Sun, Ge Yang, Jian-xue |
author_facet | Hou, Xi-xi Gong, Xiao-qing Mao, Long-fei Sun, Ge Yang, Jian-xue |
author_sort | Hou, Xi-xi |
collection | PubMed |
description | Erlotinib is a highly specific and reversible epidermal growth factor receptor tyrosine kinase inhibitor for the targeted therapy of non-small-cell lung cancer (NSCLC) However, the efficacy of erlotinib is limited because the development of drug resistance during chemotherapy. Indoleamine 2,3-dioxygenase-1 (IDO1) is a rate-limiting tryptophan catabolic enzyme that is activated in many human cancers. In this study, we designed a series of erlotinib-based 1,2,3-triazole compounds by combining erlotinib with phenyl or benzyl azide. Attentive FP prediction model was used to predict the bioactivity of those compounds. We discovered that most of the erlotinib-based 1,2,3-triazole compounds are capable of suppressing IDO1 activities in vitro experiments. Among them, compound 14b (IC(50) = 0.59 ± 0.05 μM) had the strongest inhibitory effect on IDO1. In addition, compound 14b significantly inhibited tumor growth comparable to the antitumor activity of erlotinib and the IDO1 inhibitor epacadostat in murine tumor models. |
format | Online Article Text |
id | pubmed-9399373 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93993732022-08-25 Design, synthesis and biological evaluation of erlotinib-based IDO1 inhibitors Hou, Xi-xi Gong, Xiao-qing Mao, Long-fei Sun, Ge Yang, Jian-xue Front Pharmacol Pharmacology Erlotinib is a highly specific and reversible epidermal growth factor receptor tyrosine kinase inhibitor for the targeted therapy of non-small-cell lung cancer (NSCLC) However, the efficacy of erlotinib is limited because the development of drug resistance during chemotherapy. Indoleamine 2,3-dioxygenase-1 (IDO1) is a rate-limiting tryptophan catabolic enzyme that is activated in many human cancers. In this study, we designed a series of erlotinib-based 1,2,3-triazole compounds by combining erlotinib with phenyl or benzyl azide. Attentive FP prediction model was used to predict the bioactivity of those compounds. We discovered that most of the erlotinib-based 1,2,3-triazole compounds are capable of suppressing IDO1 activities in vitro experiments. Among them, compound 14b (IC(50) = 0.59 ± 0.05 μM) had the strongest inhibitory effect on IDO1. In addition, compound 14b significantly inhibited tumor growth comparable to the antitumor activity of erlotinib and the IDO1 inhibitor epacadostat in murine tumor models. Frontiers Media S.A. 2022-08-10 /pmc/articles/PMC9399373/ /pubmed/36034879 http://dx.doi.org/10.3389/fphar.2022.940704 Text en Copyright © 2022 Hou, Gong, Mao, Sun and Yang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Hou, Xi-xi Gong, Xiao-qing Mao, Long-fei Sun, Ge Yang, Jian-xue Design, synthesis and biological evaluation of erlotinib-based IDO1 inhibitors |
title | Design, synthesis and biological evaluation of erlotinib-based IDO1 inhibitors |
title_full | Design, synthesis and biological evaluation of erlotinib-based IDO1 inhibitors |
title_fullStr | Design, synthesis and biological evaluation of erlotinib-based IDO1 inhibitors |
title_full_unstemmed | Design, synthesis and biological evaluation of erlotinib-based IDO1 inhibitors |
title_short | Design, synthesis and biological evaluation of erlotinib-based IDO1 inhibitors |
title_sort | design, synthesis and biological evaluation of erlotinib-based ido1 inhibitors |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9399373/ https://www.ncbi.nlm.nih.gov/pubmed/36034879 http://dx.doi.org/10.3389/fphar.2022.940704 |
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