dBET6 is a novel, orally active BRD4 degrader that suppresses the transcription and expression of oncogenes such as c-Myc[1-2]. dBET6 can be used in research related to cancers such as acute myeloid leukemia[3-4].
In vitro, when chronic myeloid leukemia cells (KU812, K562, KCL22, and KCL22T315I) were treated with dBET6 (1nM–50μM) for 48 hours, dBET6 significantly inhibited cell proliferation, induced apoptosis, and blocked MYC expression. dBET6 also synergized with BCR::ABL1 tyrosine kinase inhibitors to overcome drug resistance[5]. When various acute myeloid leukemia and acute lymphoblastic leukemia cell lines (KG1, HL60, MOLM-13, MV4-11, BV-173, NALM-1, etc.) and primary patient-derived AML and ALL cells were treated with dBET6 (0.05μM to 1μM) for 0 to 48 hours. dBET6 significantly inhibited cell growth and viability and induced apoptosis. Additionally, dBET6 overcame osteoblast-induced chemotherapy resistance and suppressed interferon-gamma and tumor necrosis factor-alpha-induced PD-L1 checkpoint antigen expression[6].
In vivo, in a light-induced retinal degeneration model, BALB/cJ and C57BL/6J mice received intraperitoneal injections of dBET6 (10mg/kg) once one hour before light exposure and again 24 hours after exposure. dBET6 significantly improved retinal function and visual sensitivity, inhibited light damage-induced retinal thinning, photoreceptor cell death, and microglia/macrophage activation, and reduced cGAS-STING pathway activity[7]. In a T-ALL xenograft mouse model, dBET6 (7.5mg/kg; intraperitoneal injection twice daily) was administered continuously for 14–18 days. dBET6 significantly reduced the leukemia burden and prolonged survival in the mice[8].
References:
[1] Winter GE, Mayer A, Buckley DL, et al. BET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment. Mol Cell. 2017 Jul 6;67(1):5-18.e19.
[2] Bauer K, Berghoff AS, Preusser M, et al. Degradation of BRD4 - a promising treatment approach not only for hematologic but also for solid cancer. Am J Cancer Res. 2021 Feb 1;11(2):530-545.
[3] Chen Z, Feng Z, Wang S, et al. Engineering Metal-Organic-Framework-Based STING Nanoagonists for PROTAC-Enhanced Cancer Chemo-Metalloimmunotherapy. Adv Sci (Weinh). 2026 Jan;13(2):e15006.
[4] Yu H, Zhao J, Wu D, et al. Exosome encapsulated albumin nanoparticles target delivery of DBET6 as a treatment for triple-negative breast cancer. PLoS One. 2026 Jan 12;21(1):e0335890.
[5] Peter B, Eisenwort G, Sadovnik I, et al. BRD4 degradation blocks expression of MYC and multiple forms of stem cell resistance in Ph+ chronic myeloid leukemia. Am J Hematol. 2022 Sep;97(9):1215-1225.
[6] Bauer K, Hauswirth A, Gleixner KV, et al. BRD4 degraders may effectively counteract therapeutic resistance of leukemic stem cells in AML and ALL. Am J Hematol. 2024 Sep;99(9):1721-1731.
[7] Zhu X, Liu W, Tang X, et al. The BET PROTAC inhibitor dBET6 protects against retinal degeneration and inhibits the cGAS-STING in response to light damage. J Neuroinflammation. 2023 May 22;20(1):119.
[8] Xu L, Chen Y, Mayakonda A, et al. Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma. Proc Natl Acad Sci U S A. 2018 May 29;115(22):E5086-E5095.
dBET6是一种新型的、具有口服活性的BRD4降解剂，可抑制c-Myc等致癌基因的转录和表达[1-2]。dBET6可用于急性髓系白血病等癌症的相关研究[3-4]。
在体外，dBET6（1nM-50μM）处理慢性髓系白血病细胞（KU812、K562、KCL22及KCL22T315I）48小时，dBET6显著抑制细胞的增殖并诱导凋亡，同时阻断MYC表达，且与BCR::ABL1酪氨酸激酶抑制剂协同克服耐药性[5]。dBET6（0.05μM至1μM）处理多种急性髓系白血病和急性淋巴细胞白血病细胞系（KG1，HL60，MOLM-13，MV4-11，BV-173，NALM-1等）以及原代患者来源的AML和ALL细胞0至48小时，dBET6可显著抑制细胞生长与活力，并诱导细胞凋亡。dBET6能克服成骨细胞诱导的化疗耐药性，并抑制干扰素-γ和肿瘤坏死因子-α诱导的PD-L1检查点抗原表达[6]。
在体内，在光诱导视网膜变性模型中，腹腔注射dBET6（10mg/kg）处理BALB/cJ和C57BL/6J小鼠（光照前1小时及光照后24小时各注射一次），dBET6显著改善视网膜功能和视觉灵敏度，抑制光损伤诱导的视网膜厚度减少、光感受器细胞死亡及小胶质细胞/巨噬细胞活化，并降低cGAS-STING通路活性[7]。dBET6（7.5mg/kg；一日两次腹腔注射）持续处理14-18天，处理T-ALL异种移植模型的小鼠。dBET6显著降低了小鼠的白血病负荷，并延长了小鼠的生存期[8]。