Cargando…

Oncolytic strategy using new bifunctional HDACs/BRD4 inhibitors against virus-associated lymphomas

Primary effusion lymphoma (PEL) caused by Kaposi sarcoma–associated herpesvirus (KSHV) is an aggressive malignancy with poor prognosis even under chemotherapy. Currently, there is no specific treatment for PEL therefore requiring new therapies. Both histone deacetylases (HDACs) and bromodomain-conta...

Descripción completa

Detalles Bibliográficos
Autores principales: Chen, Jungang, Wang, Zhengyu, Phuc, Tran, Xu, Zhigang, Yang, Donglin, Chen, Zhengzhu, Lin, Zhen, Kendrick, Samantha, Dai, Lu, Li, Hong-yu, Qin, Zhiqiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9879403/
https://www.ncbi.nlm.nih.gov/pubmed/36638143
http://dx.doi.org/10.1371/journal.ppat.1011089
_version_ 1784878679640244224
author Chen, Jungang
Wang, Zhengyu
Phuc, Tran
Xu, Zhigang
Yang, Donglin
Chen, Zhengzhu
Lin, Zhen
Kendrick, Samantha
Dai, Lu
Li, Hong-yu
Qin, Zhiqiang
author_facet Chen, Jungang
Wang, Zhengyu
Phuc, Tran
Xu, Zhigang
Yang, Donglin
Chen, Zhengzhu
Lin, Zhen
Kendrick, Samantha
Dai, Lu
Li, Hong-yu
Qin, Zhiqiang
author_sort Chen, Jungang
collection PubMed
description Primary effusion lymphoma (PEL) caused by Kaposi sarcoma–associated herpesvirus (KSHV) is an aggressive malignancy with poor prognosis even under chemotherapy. Currently, there is no specific treatment for PEL therefore requiring new therapies. Both histone deacetylases (HDACs) and bromodomain-containing protein 4 (BRD4) have been found as therapeutic targets for PEL through inducing viral lytic reactivation. However, the strategy of dual targeting with one agent and potential synergistic effects have never been explored. In the current study, we first demonstrated the synergistic effect of concurrently targeting HDACs and BRD4 on KSHV reactivation by using SAHA or entinostat (HDACs inhibitors) and (+)-JQ1 (BRD4 inhibitor), which indicated dual blockage of HDACs/BRD4 is a viable therapeutic approach. We were then able to rationally design and synthesize a series of new small-molecule inhibitors targeting HDACs and BRD4 with a balanced activity profile by generating a hybrid of the key binding motifs between (+)-JQ1 and entinostat or SAHA. Upon two iterative screenings of optimized compounds, a pair of epimers, 009P1 and 009P2, were identified to better inhibit the growth of KSHV positive lymphomas compared to (+)-JQ1 or SAHA alone at low nanomolar concentrations, but not KSHV negative control cells or normal cells. Mechanistic studies of 009P1 and 009P2 demonstrated significantly enhanced viral reactivation, cell cycle arrest and apoptosis in KSHV+ lymphomas through dually targeting HDACs and BRD4 signaling activities. Importantly, in vivo preclinical studies showed that 009P1 and 009P2 dramatically suppressed KSHV+ lymphoma progression with oral bioavailability and minimal visible toxicity. These data together provide a novel strategy for the development of agents for inducing lytic activation-based therapies against these viruses-associated malignancies.
format Online
Article
Text
id pubmed-9879403
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-98794032023-01-27 Oncolytic strategy using new bifunctional HDACs/BRD4 inhibitors against virus-associated lymphomas Chen, Jungang Wang, Zhengyu Phuc, Tran Xu, Zhigang Yang, Donglin Chen, Zhengzhu Lin, Zhen Kendrick, Samantha Dai, Lu Li, Hong-yu Qin, Zhiqiang PLoS Pathog Research Article Primary effusion lymphoma (PEL) caused by Kaposi sarcoma–associated herpesvirus (KSHV) is an aggressive malignancy with poor prognosis even under chemotherapy. Currently, there is no specific treatment for PEL therefore requiring new therapies. Both histone deacetylases (HDACs) and bromodomain-containing protein 4 (BRD4) have been found as therapeutic targets for PEL through inducing viral lytic reactivation. However, the strategy of dual targeting with one agent and potential synergistic effects have never been explored. In the current study, we first demonstrated the synergistic effect of concurrently targeting HDACs and BRD4 on KSHV reactivation by using SAHA or entinostat (HDACs inhibitors) and (+)-JQ1 (BRD4 inhibitor), which indicated dual blockage of HDACs/BRD4 is a viable therapeutic approach. We were then able to rationally design and synthesize a series of new small-molecule inhibitors targeting HDACs and BRD4 with a balanced activity profile by generating a hybrid of the key binding motifs between (+)-JQ1 and entinostat or SAHA. Upon two iterative screenings of optimized compounds, a pair of epimers, 009P1 and 009P2, were identified to better inhibit the growth of KSHV positive lymphomas compared to (+)-JQ1 or SAHA alone at low nanomolar concentrations, but not KSHV negative control cells or normal cells. Mechanistic studies of 009P1 and 009P2 demonstrated significantly enhanced viral reactivation, cell cycle arrest and apoptosis in KSHV+ lymphomas through dually targeting HDACs and BRD4 signaling activities. Importantly, in vivo preclinical studies showed that 009P1 and 009P2 dramatically suppressed KSHV+ lymphoma progression with oral bioavailability and minimal visible toxicity. These data together provide a novel strategy for the development of agents for inducing lytic activation-based therapies against these viruses-associated malignancies. Public Library of Science 2023-01-13 /pmc/articles/PMC9879403/ /pubmed/36638143 http://dx.doi.org/10.1371/journal.ppat.1011089 Text en © 2023 Chen et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Chen, Jungang
Wang, Zhengyu
Phuc, Tran
Xu, Zhigang
Yang, Donglin
Chen, Zhengzhu
Lin, Zhen
Kendrick, Samantha
Dai, Lu
Li, Hong-yu
Qin, Zhiqiang
Oncolytic strategy using new bifunctional HDACs/BRD4 inhibitors against virus-associated lymphomas
title Oncolytic strategy using new bifunctional HDACs/BRD4 inhibitors against virus-associated lymphomas
title_full Oncolytic strategy using new bifunctional HDACs/BRD4 inhibitors against virus-associated lymphomas
title_fullStr Oncolytic strategy using new bifunctional HDACs/BRD4 inhibitors against virus-associated lymphomas
title_full_unstemmed Oncolytic strategy using new bifunctional HDACs/BRD4 inhibitors against virus-associated lymphomas
title_short Oncolytic strategy using new bifunctional HDACs/BRD4 inhibitors against virus-associated lymphomas
title_sort oncolytic strategy using new bifunctional hdacs/brd4 inhibitors against virus-associated lymphomas
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9879403/
https://www.ncbi.nlm.nih.gov/pubmed/36638143
http://dx.doi.org/10.1371/journal.ppat.1011089
work_keys_str_mv AT chenjungang oncolyticstrategyusingnewbifunctionalhdacsbrd4inhibitorsagainstvirusassociatedlymphomas
AT wangzhengyu oncolyticstrategyusingnewbifunctionalhdacsbrd4inhibitorsagainstvirusassociatedlymphomas
AT phuctran oncolyticstrategyusingnewbifunctionalhdacsbrd4inhibitorsagainstvirusassociatedlymphomas
AT xuzhigang oncolyticstrategyusingnewbifunctionalhdacsbrd4inhibitorsagainstvirusassociatedlymphomas
AT yangdonglin oncolyticstrategyusingnewbifunctionalhdacsbrd4inhibitorsagainstvirusassociatedlymphomas
AT chenzhengzhu oncolyticstrategyusingnewbifunctionalhdacsbrd4inhibitorsagainstvirusassociatedlymphomas
AT linzhen oncolyticstrategyusingnewbifunctionalhdacsbrd4inhibitorsagainstvirusassociatedlymphomas
AT kendricksamantha oncolyticstrategyusingnewbifunctionalhdacsbrd4inhibitorsagainstvirusassociatedlymphomas
AT dailu oncolyticstrategyusingnewbifunctionalhdacsbrd4inhibitorsagainstvirusassociatedlymphomas
AT lihongyu oncolyticstrategyusingnewbifunctionalhdacsbrd4inhibitorsagainstvirusassociatedlymphomas
AT qinzhiqiang oncolyticstrategyusingnewbifunctionalhdacsbrd4inhibitorsagainstvirusassociatedlymphomas