2. Academic Validation
  3. Targeting oncogenic transcriptional factor c-myc by oligonucleotide PROTAC for the treatment of hepatocellular carcinoma

Targeting oncogenic transcriptional factor c-myc by oligonucleotide PROTAC for the treatment of hepatocellular carcinoma

  • Eur J Med Chem. 2024 Dec 15:280:116978. doi: 10.1016/j.ejmech.2024.116978.
Min Ai 1,  Hulin Ma 1,  Jianhua He 1,  Fuyan Xu 1,  Yue Ming 1,  Zixia Ye 1,  Qingquan Zheng 1,  Dongdong Luo 1,  Kaichuan Yang 2,  Jiao Li 1,  Chunlai Nie 3,  Wenchen Pu 4,  Yong Peng 5
Affiliations

Affiliations

  • 1 Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610064, China.
  • 2 Engineering Research Center for Pharmaceuticals and Equipments of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, 610052, China.
  • 3 Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610064, China. Electronic address: niecl1022@scu.edu.cn.
  • 4 Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610064, China. Electronic address: pu_vincent@scu.edu.cn.
  • 5 Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610064, China; Frontier Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, China. Electronic address: yongpeng@scu.edu.cn.
PMID: 39447458 DOI: 10.1016/j.ejmech.2024.116978
Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, but effective therapeutic strategies are limited. Transcriptional factor c-Myc plays an oncogenic role in tumorigenesis and is an attractive target for HCC treatment. However, targeted therapy against c-Myc remains challenging. Herein, by conjugating VH032 with an optimized DNA sequence that recognized c-Myc complex, we discovered oligonucleotide-based proteolysis targeting chimeras (PROTACs), termed as MP-16 and MP-17, which effectively induced degradation of c-Myc. Mechanically, MP-16 or MP-17 directly interacted with c-Myc complex to form VHL/PROTAC/c-Myc ternary complex, and triggered c-Myc degradation by recruiting ubiquitin-proteasome system, suppressing cell proliferation of HCC cells. In mice model, MP-16 or MP-17 significantly inhibited HCC tumor growth and exhibited promising drug safety. This work provided novel oligonucleotide PROTACs that degraded c-Myc, giving a new lead structure for HCC therapy.

Keywords

Hepatocellular carcinoma; Oligonucleotide; PROTAC; Targeted therapy; c-Myc.

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