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

作     者：Aiping Chen Yue Zhong Yunxiao Liu Zhancheng Xie Hanyu Wu Wei Shi Wenlong Huang Renxiang Tan Hai Qian Aiping Chen;Yue Zhong;Yunxiao Liu;Zhancheng Xie;Hanyu Wu;Wei Shi;Wenlong Huang;Renxiang Tan;Hai Qian

作者机构：College of PharmacyNanjing University of Chinese MedicineNanjing 210023China Center of Drug DiscoveryState Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China Jiangsu Key Laboratory of Drug Discovery for Metabolic DiseaseChina Pharmaceutical UniversityNanjing 210009China 

出 版 物：《Chinese Chemical Letters》 (中国化学快报（英文版）)

年 卷 期：2023年第34卷第6期

页      面：426-431页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 0703[理学-化学] 10[医学] 100701[医学-药物化学] 

基　　金：the National Science Foundation of China(Nos.81872733,82173674,and 81872734) the Research&Development Project in Key Areas of Guangdong Province(No.2019B020203003)for supporting this study。 

主　　题：Acute myeloid leukemia BRD4 PROTACs Protein degradation Apoptosis 

摘      要：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 DC_(50)and IC_(50)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.