Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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, Ding, Ke, Ding, Jian, Xie, Hua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
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
_version_ 1784861043848118272
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
work_keys_str_mv AT songpeiran ask120067potentlysuppressesbcellortcellmalignanciesinvitroandinvivobyinhibitingbtkanditk
AT baigang ask120067potentlysuppressesbcellortcellmalignanciesinvitroandinvivobyinhibitingbtkanditk
AT chanshingpan ask120067potentlysuppressesbcellortcellmalignanciesinvitroandinvivobyinhibitingbtkanditk
AT zhangtao ask120067potentlysuppressesbcellortcellmalignanciesinvitroandinvivobyinhibitingbtkanditk
AT tonglinjiang ask120067potentlysuppressesbcellortcellmalignanciesinvitroandinvivobyinhibitingbtkanditk
AT suyi ask120067potentlysuppressesbcellortcellmalignanciesinvitroandinvivobyinhibitingbtkanditk
AT shenyanyan ask120067potentlysuppressesbcellortcellmalignanciesinvitroandinvivobyinhibitingbtkanditk
AT chenyi ask120067potentlysuppressesbcellortcellmalignanciesinvitroandinvivobyinhibitingbtkanditk
AT liuyingqiang ask120067potentlysuppressesbcellortcellmalignanciesinvitroandinvivobyinhibitingbtkanditk
AT laimengzhen ask120067potentlysuppressesbcellortcellmalignanciesinvitroandinvivobyinhibitingbtkanditk
AT ningyi ask120067potentlysuppressesbcellortcellmalignanciesinvitroandinvivobyinhibitingbtkanditk
AT tanghaotian ask120067potentlysuppressesbcellortcellmalignanciesinvitroandinvivobyinhibitingbtkanditk
AT fangyan ask120067potentlysuppressesbcellortcellmalignanciesinvitroandinvivobyinhibitingbtkanditk
AT chenyi ask120067potentlysuppressesbcellortcellmalignanciesinvitroandinvivobyinhibitingbtkanditk
AT dingke ask120067potentlysuppressesbcellortcellmalignanciesinvitroandinvivobyinhibitingbtkanditk
AT dingjian ask120067potentlysuppressesbcellortcellmalignanciesinvitroandinvivobyinhibitingbtkanditk
AT xiehua ask120067potentlysuppressesbcellortcellmalignanciesinvitroandinvivobyinhibitingbtkanditk