An ATG4B inhibitor blocks autophagy and sensitizes Sorafenib inhibition activities in HCC tumor cells

Yanqiu Xie; Shijie Fan; Dongxuan Ni; Wei Wan; Pan Xu; Yiluan Ding; Ruihan Zhang; Jing Lu; Naixia Zhang; Yuanyuan Zhang; Weilie Xiao; Kehao Zhao; Cheng Luo

doi:10.1016/j.bmc.2023.117262

An ATG4B inhibitor blocks autophagy and sensitizes Sorafenib inhibition activities in HCC tumor cells

Bioorg Med Chem. 2023 Apr 15:84:117262. doi: 10.1016/j.bmc.2023.117262. Epub 2023 Mar 27.

Authors

Yanqiu Xie¹, Shijie Fan², Dongxuan Ni³, Wei Wan⁴, Pan Xu⁴, Yiluan Ding⁴, Ruihan Zhang⁵, Jing Lu⁶, Naixia Zhang⁴, Yuanyuan Zhang⁴, Weilie Xiao⁷, Kehao Zhao⁸, Cheng Luo⁹

Affiliations

¹ School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
³ Key Laboratory of Medicinal Chemistry for Natural Resource of Ministry of Education, Yunnan Characteristic Plant Extraction Laboratory, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology and School of Medicine, Yunnan University, Kunming 650500, China; State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming 650091, China.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
⁵ Key Laboratory of Medicinal Chemistry for Natural Resource of Ministry of Education, Yunnan Characteristic Plant Extraction Laboratory, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology and School of Medicine, Yunnan University, Kunming 650500, China.
⁶ School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China.
⁷ Key Laboratory of Medicinal Chemistry for Natural Resource of Ministry of Education, Yunnan Characteristic Plant Extraction Laboratory, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology and School of Medicine, Yunnan University, Kunming 650500, China; State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming 650091, China. Electronic address: xiaoweilie@ynu.edu.cn.
⁸ School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, China. Electronic address: kehaozhao@gmail.com.
⁹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China; School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China. Electronic address: cluo@simm.ac.cn.

PMID: 37018878
DOI: 10.1016/j.bmc.2023.117262

Abstract

Autophagy related 4B (ATG4B) which regulates autophagy by promoting the formation of autophagosome through reversible modification of LC3, is closely related to cancer cell growth and drug resistance, and therefore is an attractive therapeutic target. Recently, ATG4B inhibitors have been reported, yet with drawbacks including weak potency. To discover more promising ATG4B inhibitors, we developed a high-throughput screening (HTS) assay and identified a new ATG4B inhibitor named DC-ATG4in. DC-ATG4in directly binds to ATG4B and inhibits its enzyme activity with an IC₅₀ of 3.08 ± 0.47 μM. We further confirmed that DC-ATG4in is an autophagy inhibitor and blocks autophagy induced by Sorafenib in Hepatocellular Carcinoma (HCC) cells. More importantly, combination of DC-ATG4in with Sorafenib synergized the cancer cell killing effect and proliferation inhibition activities on HCC cells. Our data suggested that inactivation of autophagy via ATG4B inhibition may be a viable strategy to sensitize existing targeted therapy such as Sorafenib in the future.

Keywords: ATG4B inhibitor; Combination therapy; DC-ATG4in; Hepatocellular Carcinoma; Sorafenib.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autophagy* / drug effects
Autophagy-Related Proteins* / antagonists & inhibitors
Autophagy-Related Proteins* / metabolism
Carcinoma, Hepatocellular / drug therapy
Cysteine Endopeptidases / metabolism
Humans
Liver Neoplasms / drug therapy
Sorafenib* / pharmacology
Sorafenib* / therapeutic use

Substances

ATG4B protein, human
Autophagy-Related Proteins
Cysteine Endopeptidases
Sorafenib