BRD4, a member of the bromodomain and extraterminal domain (BET) family, has emerged as an attractive target in multiple pathological settings. For example, recent studies have demonstrated its importance in driving the proliferation of several cancers including NUT midline carcinoma, acute myelogenous leukemia (AML), multiple myeloma, Burkitt's Lymphoma (BL), and prostate cancer. Thus, BET bromodomain inhibitors have showed promising effects in certain preclinical settings, particularly in MYC-driven hematological malignancies, such as BL. Interestingly, we found that BRD4 inhibitors lead to a rapid and robust accumulation of BRD4 that, together with the reversible nature of binding to BRD4, may account for their moderate suppression of MYC expression and inhibition of cell proliferation. To circumvent these limitations, we designed a Proteolysis Targeting Chimera (PROTAC) compound, containing a BRD4 binding moiety and an E3 ubiquitin ligase cereblon ligand. By actively engaging the E3 ligase-proteasome degradation machinery, BRD4 PROTAC leads to fast and efficient degradation of BRD4. Consequently, it is more effective than small molecule BRD4 inhibitors in suppressing MYC levels and downstream signaling, which are associated with proliferation and survival of malignant cells. More importantly, we also demonstrated that BRD4 PROTAC is more effective in inhibiting BL cell proliferation and inducing apoptosis compared to BRD4 inhibitors. Our findings strongly demonstrate that a degrader of BRD4, in the form of a cereblon-based PROTAC, provides a better and more efficient strategy in targeting BRD4 than traditional small molecule inhibitors.
Citation Format: Jing Lu, Yimin Qian, Martha Altieri, Hanqing Dong, Jing Wang, Kanak Raina, Jim Winkler, Andy Crew, Kevin Coleman, John Hines, Craig Crews. Hijacking the E3 ubiquitin ligase cereblon to create efficient BRD4 degraders. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-010. doi:10.1158/1538-7445.AM2015-LB-010
