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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Oncolytic strategy using new bifunctional HDACs/BRD4 inhibitors against virus-associated lymphomas
Jungang Chen1, Zhengyu Wang2, Tran Phuc2
1Department of Pathology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
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.
Insights
New dual-targeting drugs show promise for treating Kaposi sarcoma-associated herpesvirus (KSHV)-driven lymphomas by reactivating the virus and halting cancer growth. These novel therapies offer a potential new strategy against these aggressive malignancies.
Area of Science:
- Oncology
- Virology
- Medicinal Chemistry
Background:
- Primary effusion lymphoma (PEL) is an aggressive KSHV-associated cancer with limited treatment options.
- Histone deacetylases (HDACs) and bromodomain-containing protein 4 (BRD4) are potential therapeutic targets for PEL.
- Dual targeting of HDACs and BRD4 for synergistic effects in PEL has not been explored.
Purpose of the Study:
- To investigate the synergistic effects of concurrently targeting HDACs and BRD4 in KSHV-associated lymphomas.
- To design and synthesize novel small-molecule inhibitors targeting both HDACs and BRD4.
- To evaluate the efficacy and safety of these novel compounds in preclinical models.
Main Methods:
- Compounds (+)-JQ1 (BRD4 inhibitor) and SAHA/entinostat (HDACs inhibitors) were used to demonstrate synergistic effects.
- A series of hybrid small-molecule inhibitors were designed and synthesized by combining key binding motifs.
- Iterative screening identified potent epimers (009P1 and 009P2) with enhanced activity against KSHV+ lymphomas.
- In vitro and in vivo studies assessed viral reactivation, cell cycle arrest, apoptosis, tumor growth inhibition, and toxicity.
Main Results:
- Concurrent targeting of HDACs and BRD4 demonstrated synergistic KSHV reactivation.
- Novel hybrid compounds 009P1 and 009P2 potently inhibited KSHV+ lymphoma cell growth at nanomolar concentrations.
- These compounds induced enhanced viral reactivation, cell cycle arrest, and apoptosis in KSHV+ lymphomas.
- In vivo studies showed significant suppression of KSHV+ lymphoma progression with oral bioavailability and minimal toxicity.
Conclusions:
- Dual targeting of HDACs and BRD4 represents a viable therapeutic strategy for KSHV-associated malignancies.
- Novel compounds 009P1 and 009P2 are promising candidates for developing new PEL therapies.
- This approach offers a novel strategy for lytic activation-based therapies against virus-associated cancers.
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