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ASK120067 potently suppresses B-cell or T-cell malignancies in vitro and in vivo by inhibiting BTK and ITK
Hyperactivation of Bruton’s tyrosine kinase (BTK) or interleukin-2-inducible T cell kinase (ITK) has been attributed to the pathogenesis of B-cell lymphoma or T-cell leukemia, respectively, which suggests that Bruton’s tyrosine kinase and interleukin-2-inducible T cell kinase are critical targets fo...
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/PMC9799096/ https://www.ncbi.nlm.nih.gov/pubmed/36588692 http://dx.doi.org/10.3389/fphar.2022.1071114 |
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author | Song, Peiran Bai, Gang Chan, Shingpan Zhang, Tao Tong, Linjiang Su, Yi Shen, Yanyan Chen, Yi Liu, Yingqiang Lai, Mengzhen Ning, Yi Tang, Haotian Fang, Yan Chen, Yi Ding, Ke Ding, Jian Xie, Hua |
author_facet | Song, Peiran Bai, Gang Chan, Shingpan Zhang, Tao Tong, Linjiang Su, Yi Shen, Yanyan Chen, Yi Liu, Yingqiang Lai, Mengzhen Ning, Yi Tang, Haotian Fang, Yan Chen, Yi Ding, Ke Ding, Jian Xie, Hua |
author_sort | Song, Peiran |
collection | PubMed |
description | Hyperactivation of Bruton’s tyrosine kinase (BTK) or interleukin-2-inducible T cell kinase (ITK) has been attributed to the pathogenesis of B-cell lymphoma or T-cell leukemia, respectively, which suggests that Bruton’s tyrosine kinase and interleukin-2-inducible T cell kinase are critical targets for the treatment of hematological malignancies. We identified a novel third-generation epidermal growth factor receptor (EGFR) inhibitor, ASK120067 (limertinib) in our previous research, which has been applied as a new drug application against non-small cell lung cancer in China. In this work, we found that ASK120067 displayed potent in vitro inhibitory efficacy against Bruton’s tyrosine kinase protein and interleukin-2-inducible T cell kinase protein via covalent binding. In cell-based assays, ASK120067 dose-dependently suppressed Bruton’s tyrosine kinase phosphorylation and exhibited anti-proliferation potency by inducing apoptosis in numerous B-lymphoma cells. Meanwhile, it caused growth arrest and induced the apoptosis of T-cell leukemia cells by attenuating interleukin-2-inducible T cell kinase activation. Oral administration of ASK120067 led to significant tumor regression in B-cell lymphoma and T-cell leukemia xenograft models by weakening Bruton’s tyrosine kinase and interleukin-2-inducible T cell kinase signaling, respectively. Taken together, our studies demonstrated that ASK120067 exerted preclinical anti-tumor activities against B-/T-cell malignancy by targeting BTK/ITK. |
format | Online Article Text |
id | pubmed-9799096 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-97990962022-12-30 ASK120067 potently suppresses B-cell or T-cell malignancies in vitro and in vivo by inhibiting BTK and ITK Song, Peiran Bai, Gang Chan, Shingpan Zhang, Tao Tong, Linjiang Su, Yi Shen, Yanyan Chen, Yi Liu, Yingqiang Lai, Mengzhen Ning, Yi Tang, Haotian Fang, Yan Chen, Yi Ding, Ke Ding, Jian Xie, Hua Front Pharmacol Pharmacology Hyperactivation of Bruton’s tyrosine kinase (BTK) or interleukin-2-inducible T cell kinase (ITK) has been attributed to the pathogenesis of B-cell lymphoma or T-cell leukemia, respectively, which suggests that Bruton’s tyrosine kinase and interleukin-2-inducible T cell kinase are critical targets for the treatment of hematological malignancies. We identified a novel third-generation epidermal growth factor receptor (EGFR) inhibitor, ASK120067 (limertinib) in our previous research, which has been applied as a new drug application against non-small cell lung cancer in China. In this work, we found that ASK120067 displayed potent in vitro inhibitory efficacy against Bruton’s tyrosine kinase protein and interleukin-2-inducible T cell kinase protein via covalent binding. In cell-based assays, ASK120067 dose-dependently suppressed Bruton’s tyrosine kinase phosphorylation and exhibited anti-proliferation potency by inducing apoptosis in numerous B-lymphoma cells. Meanwhile, it caused growth arrest and induced the apoptosis of T-cell leukemia cells by attenuating interleukin-2-inducible T cell kinase activation. Oral administration of ASK120067 led to significant tumor regression in B-cell lymphoma and T-cell leukemia xenograft models by weakening Bruton’s tyrosine kinase and interleukin-2-inducible T cell kinase signaling, respectively. Taken together, our studies demonstrated that ASK120067 exerted preclinical anti-tumor activities against B-/T-cell malignancy by targeting BTK/ITK. Frontiers Media S.A. 2022-12-15 /pmc/articles/PMC9799096/ /pubmed/36588692 http://dx.doi.org/10.3389/fphar.2022.1071114 Text en Copyright © 2022 Song, Bai, Chan, Zhang, Tong, Su, Shen, Chen, Liu, Lai, Ning, Tang, Fang, Chen, Ding, Ding and Xie. 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 Song, Peiran Bai, Gang Chan, Shingpan Zhang, Tao Tong, Linjiang Su, Yi Shen, Yanyan Chen, Yi Liu, Yingqiang Lai, Mengzhen Ning, Yi Tang, Haotian Fang, Yan Chen, Yi Ding, Ke Ding, Jian Xie, Hua ASK120067 potently suppresses B-cell or T-cell malignancies in vitro and in vivo by inhibiting BTK and ITK |
title | ASK120067 potently suppresses B-cell or T-cell malignancies in vitro and in vivo by inhibiting BTK and ITK |
title_full | ASK120067 potently suppresses B-cell or T-cell malignancies in vitro and in vivo by inhibiting BTK and ITK |
title_fullStr | ASK120067 potently suppresses B-cell or T-cell malignancies in vitro and in vivo by inhibiting BTK and ITK |
title_full_unstemmed | ASK120067 potently suppresses B-cell or T-cell malignancies in vitro and in vivo by inhibiting BTK and ITK |
title_short | ASK120067 potently suppresses B-cell or T-cell malignancies in vitro and in vivo by inhibiting BTK and ITK |
title_sort | ask120067 potently suppresses b-cell or t-cell malignancies in vitro and in vivo by inhibiting btk and itk |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9799096/ https://www.ncbi.nlm.nih.gov/pubmed/36588692 http://dx.doi.org/10.3389/fphar.2022.1071114 |
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