Citation: Aiping Chen, Yue Zhong, Yunxiao Liu, Zhancheng Xie, Hanyu Wu, Wei Shi, Wenlong Huang, Renxiang Tan, Hai Qian. Identification of highly efficacious PROTACs targeting BRD4 against acute myeloid leukemia: Design, synthesis, and biological evaluations[J]. Chinese Chemical Letters, ;2023, 34(6): 107923. doi: 10.1016/j.cclet.2022.107923 shu

Identification of highly efficacious PROTACs targeting BRD4 against acute myeloid leukemia: Design, synthesis, and biological evaluations

Aiping Chen ^{a, 1} ,
Yue Zhong ^{b, 1} ,
Yunxiao Liu ^b ,
Zhancheng Xie ^b ,
Hanyu Wu ^b ,
Wei Shi ^b ,
Wenlong Huang ^b ,
Renxiang Tan ^{a, *,} ,
Hai Qian ^{b, c, *,}

a.
College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
b.
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
c.
Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, China

^**

rxtan@nju.edu.cn

qianhai24@163.com

Received Date: 6 August 2022
Revised Date: 12 October 2022
Accepted Date: 18 October 2022
Available Online: 28 October 2022

Figures(6)

The abnormal activation of BRD4 accelerates the progression of acute myeloid leukemia (AML), developing more precise therapeutics to intervene BRD4 promise to be an excellent opportunity to avoid current limitations of chemotherapy in clinic. Herein, a range of small-molecule PROTACs with the privileged 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one scaffold were rationally designed, which harbored different carbon or ethylenedioxy chains to degrade BRD4 mediated by the E3 ubiquitin ligase CRBN. Among them, the most potential B24 exhibited remarkable BRD4 degradation and excellent anti-proliferative activities in MV4-11 cells, with values of DC₅₀ and IC₅₀ for 0.75 nmol/L and 0.4 nmol/L, respectively, which were better than the BRD4 inhibitor (+)-JQ-1. Notably, this compound could time-dependently degrade the target protein in the BRD4-, CRBN-, and proteasome-dependent manner. Besides, B24 dramatically decreased the level of proto-oncogene c-Myc, and induced cell apoptosis by arresting the cell cycle in G0/G1 phase, down-regulating Bcl-2 and up-regulating Bax to amplify apoptotic effectors. This proof-of-concept study also highlighted the feasibility of BRD4-based PROTACs as a more powerful strategy against AML.
- Acute myeloid leukemia,
- BRD4,
- PROTACs,
- Protein degradation,
- Apoptosis
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