Cargando…

Novel STAT3 Inhibitors Targeting STAT3 Dimerization by Binding to the STAT3 SH2 Domain

Our drug discovery model has identified two novel STAT3 SH2 domain inhibitors 323–1 and 323–2 (delavatine A stereoisomers) in a series of experiments. In silico computational modeling, drug affinity responsive target stability (DARTS), and fluorescence polarization (FP) assays altogether determined...

Descripción completa

Detalles Bibliográficos
Autores principales: Hua, Yaping, Yuan, Xing, Shen, Yun-heng, Wang, Jinxin, Azeem, Waqas, Yang, Shuo, Gade, Alexandra, Lellahi, Seyed Mohammad, Øyan, Anne Margrete, Ke, Xisong, Zhang, Wei-dong, Kalland, Karl-Henning
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9196127/
https://www.ncbi.nlm.nih.gov/pubmed/35712699
http://dx.doi.org/10.3389/fphar.2022.836724
_version_ 1784727114560307200
author Hua, Yaping
Yuan, Xing
Shen, Yun-heng
Wang, Jinxin
Azeem, Waqas
Yang, Shuo
Gade, Alexandra
Lellahi, Seyed Mohammad
Øyan, Anne Margrete
Ke, Xisong
Zhang, Wei-dong
Kalland, Karl-Henning
author_facet Hua, Yaping
Yuan, Xing
Shen, Yun-heng
Wang, Jinxin
Azeem, Waqas
Yang, Shuo
Gade, Alexandra
Lellahi, Seyed Mohammad
Øyan, Anne Margrete
Ke, Xisong
Zhang, Wei-dong
Kalland, Karl-Henning
author_sort Hua, Yaping
collection PubMed
description Our drug discovery model has identified two novel STAT3 SH2 domain inhibitors 323–1 and 323–2 (delavatine A stereoisomers) in a series of experiments. In silico computational modeling, drug affinity responsive target stability (DARTS), and fluorescence polarization (FP) assays altogether determined that 323–1 and 323–2 directly target the STAT3 SH2 domain and inhibited both phosphorylated and non-phosphorylated STAT3 dimerization. Computational docking predicted that compound 323s bind to three subpockets of the STAT3 SH2 domain. The 323s inhibition of STAT3 dimerization was more potent than the commercial STAT3 SH2 domain inhibitor S3I-201 in the co-immunoprecipitation assay, correlating with computational docking data. The fluorescence polarization assay further confirmed that the compound 323s target the STAT3 SH2 domain by competitively abrogating the interaction between STAT3 and the SH2-binding peptide GpYLPQTV. Compared with S3I-201, the 323 compounds exhibited stronger inhibition of STAT3 and reduced the level of IL-6-stimulated phosphorylation of STAT3 (Tyr705) in LNCaP cells over the phosphorylation of STAT1 (Tyr701) induced by IFN-ɣ in PC3 cells or the phosphorylation of STAT1 (Ser727) in DU145 cells. Both compounds downregulated STAT3 target genes MCL1 and cyclin D1. Thus, the two compounds are promising lead compounds for the treatment of cancers with hyper-activated STAT3.
format Online
Article
Text
id pubmed-9196127
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-91961272022-06-15 Novel STAT3 Inhibitors Targeting STAT3 Dimerization by Binding to the STAT3 SH2 Domain Hua, Yaping Yuan, Xing Shen, Yun-heng Wang, Jinxin Azeem, Waqas Yang, Shuo Gade, Alexandra Lellahi, Seyed Mohammad Øyan, Anne Margrete Ke, Xisong Zhang, Wei-dong Kalland, Karl-Henning Front Pharmacol Pharmacology Our drug discovery model has identified two novel STAT3 SH2 domain inhibitors 323–1 and 323–2 (delavatine A stereoisomers) in a series of experiments. In silico computational modeling, drug affinity responsive target stability (DARTS), and fluorescence polarization (FP) assays altogether determined that 323–1 and 323–2 directly target the STAT3 SH2 domain and inhibited both phosphorylated and non-phosphorylated STAT3 dimerization. Computational docking predicted that compound 323s bind to three subpockets of the STAT3 SH2 domain. The 323s inhibition of STAT3 dimerization was more potent than the commercial STAT3 SH2 domain inhibitor S3I-201 in the co-immunoprecipitation assay, correlating with computational docking data. The fluorescence polarization assay further confirmed that the compound 323s target the STAT3 SH2 domain by competitively abrogating the interaction between STAT3 and the SH2-binding peptide GpYLPQTV. Compared with S3I-201, the 323 compounds exhibited stronger inhibition of STAT3 and reduced the level of IL-6-stimulated phosphorylation of STAT3 (Tyr705) in LNCaP cells over the phosphorylation of STAT1 (Tyr701) induced by IFN-ɣ in PC3 cells or the phosphorylation of STAT1 (Ser727) in DU145 cells. Both compounds downregulated STAT3 target genes MCL1 and cyclin D1. Thus, the two compounds are promising lead compounds for the treatment of cancers with hyper-activated STAT3. Frontiers Media S.A. 2022-05-27 /pmc/articles/PMC9196127/ /pubmed/35712699 http://dx.doi.org/10.3389/fphar.2022.836724 Text en Copyright © 2022 Hua, Yuan, Shen, Wang, Azeem, Yang, Gade, Lellahi, Øyan, Ke, Zhang and Kalland. 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
Hua, Yaping
Yuan, Xing
Shen, Yun-heng
Wang, Jinxin
Azeem, Waqas
Yang, Shuo
Gade, Alexandra
Lellahi, Seyed Mohammad
Øyan, Anne Margrete
Ke, Xisong
Zhang, Wei-dong
Kalland, Karl-Henning
Novel STAT3 Inhibitors Targeting STAT3 Dimerization by Binding to the STAT3 SH2 Domain
title Novel STAT3 Inhibitors Targeting STAT3 Dimerization by Binding to the STAT3 SH2 Domain
title_full Novel STAT3 Inhibitors Targeting STAT3 Dimerization by Binding to the STAT3 SH2 Domain
title_fullStr Novel STAT3 Inhibitors Targeting STAT3 Dimerization by Binding to the STAT3 SH2 Domain
title_full_unstemmed Novel STAT3 Inhibitors Targeting STAT3 Dimerization by Binding to the STAT3 SH2 Domain
title_short Novel STAT3 Inhibitors Targeting STAT3 Dimerization by Binding to the STAT3 SH2 Domain
title_sort novel stat3 inhibitors targeting stat3 dimerization by binding to the stat3 sh2 domain
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9196127/
https://www.ncbi.nlm.nih.gov/pubmed/35712699
http://dx.doi.org/10.3389/fphar.2022.836724
work_keys_str_mv AT huayaping novelstat3inhibitorstargetingstat3dimerizationbybindingtothestat3sh2domain
AT yuanxing novelstat3inhibitorstargetingstat3dimerizationbybindingtothestat3sh2domain
AT shenyunheng novelstat3inhibitorstargetingstat3dimerizationbybindingtothestat3sh2domain
AT wangjinxin novelstat3inhibitorstargetingstat3dimerizationbybindingtothestat3sh2domain
AT azeemwaqas novelstat3inhibitorstargetingstat3dimerizationbybindingtothestat3sh2domain
AT yangshuo novelstat3inhibitorstargetingstat3dimerizationbybindingtothestat3sh2domain
AT gadealexandra novelstat3inhibitorstargetingstat3dimerizationbybindingtothestat3sh2domain
AT lellahiseyedmohammad novelstat3inhibitorstargetingstat3dimerizationbybindingtothestat3sh2domain
AT øyanannemargrete novelstat3inhibitorstargetingstat3dimerizationbybindingtothestat3sh2domain
AT kexisong novelstat3inhibitorstargetingstat3dimerizationbybindingtothestat3sh2domain
AT zhangweidong novelstat3inhibitorstargetingstat3dimerizationbybindingtothestat3sh2domain
AT kallandkarlhenning novelstat3inhibitorstargetingstat3dimerizationbybindingtothestat3sh2domain