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Targeting Myc through BET-PROTAC elicits potent anti-lymphoma activity in diffuse large B cell lymphoma
Hui Wang1,2, Ximei Wu1,2, Jingjing Gao1,2
1Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, China.
Abstract:
Diffuse large B cell lymphoma (DLBCL) presents a great challenge in the clinic due to its poor prognosis. Prior research has identified c-Myc as a promising therapeutic target in DLBCL; however, direct targeting of c-Myc protein has proven challenging. The bromodomain and extraterminal (BET) protein family, which acts as transcriptional and epigenetic regulators, plays a crucial role in super-enhancer organization and transcriptional regulation of oncogenic drivers like c-Myc, offering an alternative approach. Recently developed BET proteolysis targeting chimera (PROTAC) compounds can rapidly and effectively degrade BET proteins and potentially offer a more durable effect than traditional BET inhibitors. In this work, we compared the anti-tumor activity of a BET PROTAC, ARV-825, with a BET inhibitor, JQ1, in DLBCL. Cell proliferation was assessed by CCK-8 assay, apoptosis was evaluated by Annexin V/PI staining, and the cell cycle was analyzed by staining DNA with propidium iodide (PI). Western blotting was used to determine the expression levels of BET family proteins and its downstream regulatory gene c-Myc, and the in vivo SCID mouse model implanted with SU-DHL-4 cells was used to analyze the in vivo drug efficacy. Our results showed that ARV-825 was superior to JQ1 in inhibiting DLBCL cell proliferation, inducing apoptosis, promoting cell cycle arrest, and prolonging survival. Notably, ARV-825 was more effective at downregulating c-Myc and BET protein levels than JQ1 in both in vitro and in vivo experiments. These evidences suggest that BET-PROTACs may offer a promising novel strategy for the clinical treatment of DLBCL.
Insights
BET proteolysis targeting chimeras (PROTACs) show superior anti-tumor activity against diffuse large B cell lymphoma (DLBCL) compared to traditional inhibitors. ARV-825, a BET PROTAC, effectively degrades c-Myc and BET proteins, offering a promising new strategy for DLBCL treatment.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Diffuse large B cell lymphoma (DLBCL) has a poor prognosis, with c-Myc identified as a key therapeutic target.
- Directly targeting c-Myc is challenging; however, the bromodomain and extraterminal (BET) protein family regulates c-Myc and offers an alternative therapeutic avenue.
- BET proteolysis targeting chimeras (PROTACs) offer a novel approach to degrade BET proteins, potentially providing more durable effects than BET inhibitors.
Purpose of the Study:
- To compare the anti-tumor efficacy of a BET PROTAC (ARV-825) with a BET inhibitor (JQ1) in DLBCL.
- To evaluate the impact of ARV-825 and JQ1 on DLBCL cell proliferation, apoptosis, cell cycle, and c-Myc/BET protein levels.
- To assess the in vivo efficacy of ARV-825 in a DLBCL mouse model.
Main Methods:
- Cell proliferation assays (CCK-8), apoptosis analysis (Annexin V/PI staining), and cell cycle analysis (PI staining).
- Western blotting to determine BET family protein and c-Myc expression levels.
- In vivo efficacy studies using a SCID mouse model implanted with SU-DHL-4 cells.
Main Results:
- ARV-825 demonstrated superior inhibition of DLBCL cell proliferation, enhanced apoptosis induction, and promoted cell cycle arrest compared to JQ1.
- ARV-825 was more effective in downregulating both BET protein and c-Myc levels than JQ1, in vitro and in vivo.
- ARV-825 treatment led to prolonged survival in the in vivo mouse model.
Conclusions:
- BET PROTACs, exemplified by ARV-825, exhibit significant anti-tumor activity against DLBCL.
- ARV-825's ability to effectively degrade BET proteins and c-Myc suggests its potential as a novel therapeutic strategy for DLBCL.
- These findings support the clinical investigation of BET PROTACs for treating diffuse large B cell lymphoma.
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