Targeting Myc through BET-PROTAC elicits potent anti-lymphoma activity in diffuse large B cell lymphoma

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.

Keywords: BET; C-Myc; Diffuse large B cell lymphoma; Inhibitor; PROTAC; Protein degradation.