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

The abnormal activation of BRD4 accelerates the progression of acute myeloid leukemia (AML), develop-ing 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 car-bon 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 tar-get 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.(c) 2023 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Automated summary

The abnormal activation of BRD4 accelerates the progression of acute myeloid leukemia (AML). A range of small-molecule PROTACs were rationally designed to degrade BRD4 mediated by the E3 ubiquitin ligase CRBN. Among them, B24 exhibited remarkable BRD4 degradation and excellent anti-proliferative activities in MV4-11 cells, surpassing the effect of the BRD4 inhibitor ( +)-JQ-1. B24 also induced cell apoptosis and inhibited cell proliferation by down-regulating c-Myc and up-regulating Bax.