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

Hepatocellular carcinoma Oligonucleotide PROTAC Targeted therapy c-Myc

Journal

European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510

Informations de publication

Date de publication:
18 Oct 2024
Historique:
received: 02 09 2024
revised: 08 10 2024
accepted: 16 10 2024
medline: 25 10 2024
pubmed: 25 10 2024
entrez: 24 10 2024
Statut: aheadofprint

Résumé

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.

Identifiants

DOI: 10.1016/j.ejmech.2024.116978 PMID: 39447458
pubmed: 39447458
pii: S0223-5234(24)00860-2
doi: 10.1016/j.ejmech.2024.116978
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

116978

Informations de copyright

Copyright © 2024 Elsevier Masson SAS. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Auteurs

Min Ai (M)

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.

Hulin Ma (H)

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.

Jianhua He (J)

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.

Fuyan Xu (F)

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.

Yue Ming (Y)

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.

Zixia Ye (Z)

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.

Qingquan Zheng (Q)

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.

Dongdong Luo (D)

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.

Kaichuan Yang (K)

Engineering Research Center for Pharmaceuticals and Equipments of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, 610052, China.

Jiao Li (J)

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.

Chunlai Nie (C)

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.

Wenchen Pu (W)

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.

Yong Peng (Y)

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.

Classifications MeSH