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

Min Ai; Hulin Ma; Jianhua He; Fuyan Xu; Yue Ming; Zixia Ye; Qingquan Zheng; Dongdong Luo; Kaichuan Yang; Jiao Li; Chunlai Nie; Wenchen Pu; Yong Peng

doi:10.1016/j.ejmech.2024.116978

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

Eur J Med Chem. 2024 Oct 18:280:116978. doi: 10.1016/j.ejmech.2024.116978. Online ahead of print.

Authors

Min Ai¹, Hulin Ma¹, Jianhua He¹, Fuyan Xu¹, Yue Ming¹, Zixia Ye¹, Qingquan Zheng¹, Dongdong Luo¹, Kaichuan Yang², Jiao Li¹, Chunlai Nie³, Wenchen Pu⁴, Yong Peng⁵

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.