YZL-51N functions as a selective inhibitor of SIRT7 by NAD+ competition to impede DNA damage repair
Tian-Shu Kang,
Yong-Ming Yan,
Yuan Tian,
Jun Zhang,
Minghui Zhang,
Yuxin Shu,
Jinbo Huang,
Jing He,
Cheng-Tian Tao,
Qian Zhu,
Jinke Gu,
Xiaopeng Lu,
Yong-Xian Cheng,
Wei-Guo Zhu
Affiliations
Tian-Shu Kang
International Cancer Center, Department of Biochemistry and Molecular Biology, Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University Medical School, Shenzhen 518055, China
Yong-Ming Yan
International Cancer Center, Department of Biochemistry and Molecular Biology, Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University Medical School, Shenzhen 518055, China
Yuan Tian
International Cancer Center, Department of Biochemistry and Molecular Biology, Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University Medical School, Shenzhen 518055, China; Department Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518055, China
Jun Zhang
International Cancer Center, Department of Biochemistry and Molecular Biology, Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University Medical School, Shenzhen 518055, China; Department Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518055, China
Minghui Zhang
International Cancer Center, Department of Biochemistry and Molecular Biology, Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University Medical School, Shenzhen 518055, China
Yuxin Shu
International Cancer Center, Department of Biochemistry and Molecular Biology, Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University Medical School, Shenzhen 518055, China
Jinbo Huang
International Cancer Center, Department of Biochemistry and Molecular Biology, Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University Medical School, Shenzhen 518055, China
Jing He
International Cancer Center, Department of Biochemistry and Molecular Biology, Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University Medical School, Shenzhen 518055, China
Cheng-Tian Tao
International Cancer Center, Department of Biochemistry and Molecular Biology, Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University Medical School, Shenzhen 518055, China
Qian Zhu
International Cancer Center, Department of Biochemistry and Molecular Biology, Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University Medical School, Shenzhen 518055, China; Department Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518055, China
Jinke Gu
International Cancer Center, Department of Biochemistry and Molecular Biology, Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University Medical School, Shenzhen 518055, China
Xiaopeng Lu
International Cancer Center, Department of Biochemistry and Molecular Biology, Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University Medical School, Shenzhen 518055, China; Department Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518055, China; Corresponding author
Yong-Xian Cheng
International Cancer Center, Department of Biochemistry and Molecular Biology, Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University Medical School, Shenzhen 518055, China; Department Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518055, China; Corresponding author
Wei-Guo Zhu
International Cancer Center, Department of Biochemistry and Molecular Biology, Institute for Inheritance-Based Innovation of Chinese Medicine, School of Pharmaceutical Sciences, Shenzhen University Medical School, Shenzhen 518055, China; Department Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518055, China; Corresponding author
Summary: The NAD+-dependent deacetylase SIRT7 is a pivotal regulator of DNA damage response (DDR) and a promising drug target for developing cancer therapeutics. However, limited progress has been made in SIRT7 modulator discovery. Here, we applied peptide-based deacetylase platforms for SIRT7 enzymatic evaluation and successfully identified a potent SIRT7 inhibitor YZL-51N. We initially isolated bioactive YZL-51N from cockroach (Periplaneta americana) extracts and then developed the de novo synthesis of this compound. Further investigation revealed that YZL-51N impaired SIRT7 enzymatic activities through occupation of the NAD+ binding pocket. YZL-51N attenuated DNA damage repair induced by ionizing radiation (IR) in colorectal cancer cells and exhibited a synergistic anticancer effect when used in combination with etoposide. Overall, our study not only identified YZL-51N as a selective SIRT7 inhibitor from insect resources, but also confirmed its potential use in combined chemo-radiotherapy by interfering in the DNA damage repair process.
