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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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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