BETd-260 (ZBC 260) is a heterobifunctional small molecule compound designed based on proteolysis-targeting chimera (PROTAC) technology, acting by linking a Cereblon ligand and a BET ligand[1, 2]. BETd-260 effectively induces the degradation of bromodomain and extraterminal domain (BET) family proteins such as BRD2, BRD3, and BRD4, significantly inhibiting tumor cell proliferation and inducing apoptosis[3, 4].
In vitro, treatment of hepatocellular carcinoma cell lines (HepG2 and BEL-7402 cells) with BETd-260 (10, 30, 100nM) for 48h significantly induced apoptosis in both cell lines, inhibited the expression of anti-apoptotic genes Mcl-1, Bcl-2, and c-Myc, increased the expression of the pro-apoptotic gene Bad, and disrupted mitochondrial membrane integrity[5]. Treatment of osteosarcoma cell lines (MNNG/HOS and Saos-2 cells) with BETd-260 (3nM) for 24h completely depleted BRD3 and BRD4 in MNNG/HOS and Saos-2 cells and significantly inhibited the expression level of BRD2 protein[6].
In vivo, BETd-260 (5mg/kg) administered intravenously to hepatocellular carcinoma (HCC) xenograft mice significantly inhibited the growth of xenograft tumors and induced apoptosis in tumor tissue cells[5].
References:
[1] Fuchs O, Bokorova R. Rationale of targeting protein cereblon as a potential strategy for cancer treatment[J]. Drugs of the Future, 2020, 45(5): 305-317.
[2] Yang C Y, Qin C, Bai L, et al. Small-molecule PROTAC degraders of the Bromodomain and Extra Terminal (BET) proteins—A review[J]. Drug Discovery Today: Technologies, 2019, 31: 43-51.
[3] Cai M, Dong J, Li H, et al. Recent developments in targeting bromodomain and extra terminal domain proteins for cancer therapeutics[J]. Current Medicinal Chemistry, 2022, 29(25): 4391-4409.
[4] Bai L, Zhou B, Yang C Y, et al. Targeted degradation of BET proteins in triple-negative breast cancer[J]. Cancer research, 2017, 77(9): 2476-2487.
[5] Zhang H, Li G, Zhang Y, et al. Targeting BET proteins with a PROTAC molecule elicits potent anticancer activity in HCC cells[J]. Frontiers in oncology, 2020, 9: 1471.
[6] Shi C, Zhang H, Wang P, et al. PROTAC induced-BET protein degradation exhibits potent anti-osteosarcoma activity by triggering apoptosis[J]. Cell death & disease, 2019, 10(11): 815.
BETd-260 (ZBC 260)是一种基于蛋白水解靶向嵌合体（PROTAC）技术设计的异双功能小分子化合物，通过连接Cereblon配体和BET配体来发挥作用[1, 2]。BETd-260 (ZBC 260)能够有效诱导BRD2、BRD3和BRD4等溴化结构域和超终端结构域（BET）家族蛋白的降解，显著抑制肿瘤细胞增殖与诱导细胞凋亡[3, 4]。
在体外，BETd-260（10, 30, 100nM）处理肝癌细胞系（HepG2、BEL-7402细胞）48h，显著诱导了两种细胞凋亡，抑制了抗凋亡基因Mcl-1、Bcl-2、c-Myc的表达，增加了促凋亡基因Bad的表达，破坏了线粒体膜完整性[5]。BETd-260（3nM）处理骨肉瘤细胞系（MNNG/HOS和Saos-2细胞）24h，完全耗竭了MNNG/HOS和Saos-2细胞中的BRD3和BRD4，并显著抑制了BRD2蛋白的表达水平[6]。
在体内，BETd-260（5mg/kg）通过静脉注射治疗肝细胞癌（HCC）异种移植小鼠，显著抑制了小鼠体内异种移植肿瘤的生长，诱导了肿瘤组织细胞凋亡[5]。