A Novel BRD Family PROTAC Inhibitor dBET1 Exerts Great Anti-Cancer Effects by Targeting c-MYC in Acute Myeloid Leukemia Cells.
A Novel BRD Family PROTAC Inhibitor dBET1 Exerts Great Anti-Cancer Effects by Targeting c-MYC in Acute Myeloid Leukemia Cells.
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新型 BRD 家族 PROTAC 抑制剂 dBET1 通过靶向急性髓系白血病细胞中的 c-MYC 发挥出色的抗癌作用
DOI：
10.3389/pore.2022.1610447
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发表时间：
2022
影响因子：
2.8
通讯作者：
Hu, Shaoyan
中科院分区：
文献类型：
--
作者：
Zhang, Kunlong;Gao, Li;Wang, Jianwei;Chu, Xinran;Zhang, Zimu;Zhang, Yongping;Fang, Fang;Tao, Yanfang;Li, Xiaolu;Tian, Yuanyuan;Li, Zhiheng;Sang, Xu;Ma, Li;Lu, Lihui;Chen, Yanling;Yu, Juanjuan;Zhuo, Ran;Wu, Shuiyan;Pan, Jian;Hu, Shaoyan
急性髓性白血病（AML）是一种侵袭性造血系统恶性肿瘤，预后低于其他白血病。最近的靶向治疗为实现更好的治疗结果提供了新的机会。然而，由于AML的复杂异质性，其预后仍然令人沮丧。在这项研究中，我们首先确定了BRD 4高表达与AML患者总生存期之间的相关性。dBET 1（一种针对布罗莫结构域和末端外结构域（BET）家族成员的蛋白水解靶向嵌合体（PROTAC））对BRD 2、BRD 3和BRD 4蛋白的靶向降解显示出对代表不同AML分子亚型的Kasumi（AML 1-ETO）、NB 4（PML-RARa）、THP-1（MLL-AF 9）和MV 4 -11（MLL-AF 4）AML细胞系的细胞毒性作用。此外，我们确定dBET 1处理阻止细胞周期并增强细胞凋亡，并且c-MYC被鉴定为下游靶标。总的来说，我们的结果表明dBET 1对具有不同分子病变的AML细胞系具有广泛的抗癌作用，并为AML患者提供更多的益处。
Acute myeloid leukemia (AML) represents an aggressive hematopoietic malignancy with a prognosis inferior to that of other leukemias. Recent targeted therapies offer new opportunities to achieve better treatment outcomes. However, due to the complex heterogeneity of AML, its prognosis remains dismal. In this study, we first identified the correlation between high expression of BRD4 and overall survival of patients with AML. Targeted degradation of BRD2, BRD3, and BRD4 proteins by dBET1, a proteolysis-targeting chimera (PROTAC) against the bromodomain and extra-terminal domain (BET) family members, showed cytotoxic effects on Kasumi (AML1-ETO), NB4 (PML-RARa), THP-1 (MLL-AF9), and MV4-11 (MLL-AF4) AML cell lines representing different molecular subtypes of AML. Furthermore, we determined that dBET1 treatment arrested cell cycling and enhanced apoptosis and c-MYC was identified as the downstream target. Collectively, our results indicated that dBET1 had broad anti-cancer effects on AML cell lines with different molecular lesions and provided more benefits to patients with AML.
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影响因子：
16
作者：
Roe, Jae-Seok;Mercan, Fatih;Rivera, Keith;Pappin, Darryl J.;Vakoc, Christopher R.
通讯作者：
Vakoc, Christopher R.
影响因子：
20.3
作者：
Kawabata, Kimihito C;Zong, Hongliang;Guzman, Monica L
通讯作者：
Guzman, Monica L
影响因子：
20.3
作者：
Dovey, Oliver M.;Cooper, Jonathan L.;Vassiliou, George S.
通讯作者：
Vassiliou, George S.
影响因子：
5.7
作者：
Larrosa-Garcia M;Baer MR
通讯作者：
Baer MR
影响因子：
64.5
作者：
Delmore JE;Issa GC;Lemieux ME;Rahl PB;Shi J;Jacobs HM;Kastritis E;Gilpatrick T;Paranal RM;Qi J;Chesi M;Schinzel AC;McKeown MR;Heffernan TP;Vakoc CR;Bergsagel PL;Ghobrial IM;Richardson PG;Young RA;Hahn WC;Anderson KC;Kung AL;Bradner JE;Mitsiades CS
通讯作者：
Mitsiades CS