2. Academic Validation
  3. Discovery of ZX079 as a Dual PROTAC Degrader Targeting BRD4/CBP in Acute Myeloid Leukemia

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

  • J Med Chem. 2026 Feb 26;69(4):4132-4159. doi: 10.1021/acs.jmedchem.5c02766.
Qiuping Xiang 1 2,  Yanan Wang 3,  Mengli Gu 4,  Junchen Yao 4,  Yanping Zhang 4,  Cheng Zhang 5,  Yong Zhang 4,  Nan Xie 4,  Shengyi Qian 4,  Yan Lu 4,  Hui Hua 1 2,  Yujie Sun 1 2,  Lin Wang 4,  Manyu Guo 4,  Qiaofeng Cao 4,  Qin Zhu 4,  Yao Chen 4,  Qianyue Zhang 4,  Xintian Zhang 4,  Yuheng Wang 4,  Chuhan Zhou 4,  Shuhang Yuan 4,  Mengdie Hu 4,  Feng Li 6 7,  Shuo Yang 3 7,  Yong Xu 5,  Dongsheng Zhu 4 6
Affiliations

Affiliations

  • 1 Ningbo No. 2 Hospital, Ningbo 315010, China.
  • 2 Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo 315000, China.
  • 3 Department of Immunology, Key Laboratory of Immunoregulation and Intervention for Major Chronic Diseases of Provincial Universities, Nanjing Medical University, Nanjing 211166, China.
  • 4 Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
  • 5 China-New Zealand Joint Laboratory of Biomedicine and Health, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Biocomputing, Institute of Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 6 Department of Urology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210003, China.
  • 7 State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing 211166, China.
PMID: 41701037 DOI: 10.1021/acs.jmedchem.5c02766
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, 10k (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, 10k 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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