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

Abstract

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.

• Authors: Jungang Chen, Zhengyu Wang, Tran Phuc, Zhigang Xu, Donglin Yang, Zhengzhu Chen, Zhen Lin, Samantha Kendrick, Lu Dai, Hong-Yu Li, Zhiqiang Qin
• Journal: PLoS pathogens (PLoS Pathog) Vol. 19 Issue 1 Pg. e1011089 (01 2023) ISSN: 1553-7374 [Electronic] United States
• PMID: 36638143 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright: © 2023 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Chemical References

• Transcription Factors
• entinostat
• Nuclear Proteins
• Histone Deacetylase Inhibitors
• BRD4 protein, human
• Cell Cycle Proteins

Topics

• Humans
• Transcription Factors (metabolism)
• Nuclear Proteins (metabolism)
• Histone Deacetylase Inhibitors (pharmacology)
• Lymphoma, Primary Effusion
• Herpesvirus 8, Human (physiology)
• Sarcoma, Kaposi
• Cell Line, Tumor
• Cell Cycle Proteins (metabolism)