Discovery of ZX079 as a Dual PROTAC Degrader Targeting BRD4/CBP in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is driven by transcriptional plasticity and epigenetic dysregulation. While BET proteins have emerged as promising therapeutic targets, BET inhibitors are limited by modest clinical efficacy and resistance, potentially mediated by CBP/p300-driven compensatory mechanisms. Herein, we describe the design, synthesis, and biological evaluation of a novel series of dual BRD4/CBP PROTAC degraders. The lead compound, <b>10k</b> (ZX079), induces potent, dose- and time-dependent degradation of BRD4 and CBP and demonstrates superior suppression of oncogenic transcription and inhibition of AML cell proliferation compared with the dual BET/CBP inhibitor NEO2734. In vivo, <b>10k</b> significantly reduces tumor growth in an AML xenograft model with TGI over 90%. Collectively, these findings highlight dual degradation of BRD4 and CBP as a promising strategy for AML.

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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2026-02-17
DOI
https://doi.org/10.1021/acs.jmedchem.5c02766
Primary Topic
Protein Degradation and Inhibitors
Type
article
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0.00
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article

Discovery of ZX079 as a Dual PROTAC Degrader Targeting BRD4/CBP in Acute Myeloid Leukemia

Xintian Zhang, Yan Xu, Yujie Sun, L. Li Wang et al.
Journal of Medicinal Chemistry
Protein Degradation and Inhibitors
article

Discovery of ZX079 as a Dual PROTAC Degrader Targeting BRD4/CBP in Acute Myeloid Leukemia

Xintian Zhang, Yan Xu, Yujie Sun, L. Li Wang, Shuo Yang, Yao Chen, Yuheng Wang, Yang Xia, Qin Zhu, Junchen Yao, Hui Hua, Manyu Guo, Qiaofeng Cao, Qiuping Xiang, D M Zhu, Feng Li, Yanping Zhang, Shuhang Yuan, Chuhan Zhou, Mengli Gu, Yong Zhang, Shengyi Qian, Cheng Zhang, Qianyue Zhang, Nan Xie, Yan Lu, Mengdie Hu
article en

Abstract

Acute myeloid leukemia (AML) is driven by transcriptional plasticity and epigenetic dysregulation. While BET proteins have emerged as promising therapeutic targets, BET inhibitors are limited by modest clinical efficacy and resistance, potentially mediated by CBP/p300-driven compensatory mechanisms. Herein, we describe the design, synthesis, and biological evaluation of a novel series of dual BRD4/CBP PROTAC degraders. The lead compound, <b>10k</b> (ZX079), induces potent, dose- and time-dependent degradation of BRD4 and CBP and demonstrates superior suppression of oncogenic transcription and inhibition of AML cell proliferation compared with the dual BET/CBP inhibitor NEO2734. In vivo, <b>10k</b> significantly reduces tumor growth in an AML xenograft model with TGI over 90%. Collectively, these findings highlight dual degradation of BRD4 and CBP as a promising strategy for AML.

Journal of Medicinal ChemistryVol. 69(4)
Guangzhou Institutes of Biomedicine and Health (CN), Ningbo No. 2 Hospital (CN), Ministry of Health (OM), Institute of Immunology (HR), Medicina (PL), Second Affiliated Hospital of Nanjing Medical University (CN), State Key Laboratory of Respiratory Disease (CN), University of Chinese Academy of Sciences (CN), State Key Laboratory of Reproductive Medicine, Nanjing Medical University (CN)
Good health and well-being
Openalex Percentile: Top 52%
Protein Degradation and Inhibitors
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