Identification of highly efficacious PROTACs targeting BRD4 against acute myeloid leukemia: Design,synthesis, and biological evaluations |
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| Institution: | 1. College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China;2. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China;3. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, China;1. Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China;2. Shanghai Collaborative Innovation Center for Biomanufacturing Technology, Shanghai 200237, China;1. Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China;2. School of Pharmacy, Hubei Engineering Research Center of Traditional Chinese Medicine of South Hubei Province, Hubei University of Science and Technology, Xianning 437100, China;1. Medical Research Center, The Third People''s Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu 610031, China;2. State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China |
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| Abstract: | 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-pyrrolo1,2-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. |
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