Discovery of a novel cathepsin inhibitor with dual autophagy-inducing and metastasis-inhibiting effects on breast cancer cells |
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| Institution: | 1. Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, Shenyang 110016, PR China;2. Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China;3. Department of Pharmacy, Liaoning Vocational College of Medicine, Shenyang 110101, PR China;4. GLP Center, Shenyang Pharmaceutical University, Shenyang 110016, PR China;5. School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, PR China;1. Key Lab of Natural Medicine and Immune Engineering, Henan University, Kaifeng 475004, China;2. Institute of Chemical Biology, Henan University, Kaifeng 475004, China;3. Chemistry Department, Henan University, Kaifeng 475004, China;1. School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, 510006, PR China;2. Guangdong Cosmetics Engineering & Technology Research Center, Guangzhou, 510006, PR China;3. Guangdong Engineering Research Center for Lead Compounds & Drug Discovery, Guangzhou, 510006, PR China;1. National Reference Laboratory of Veterinary Drug Residues and MOA Key Laboratory for Detection of Veterinary Drug Residues, Wuhan, Hubei, 430070, China;2. MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei, 430070, China;1. State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University, Guilin 541004, China;2. Affiliated Hospital of Guilin Medicine University, Guilin 541004, China;1. Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, Shenyang 110016, PR China;2. Institute of Drug Research in Medicine Capital of China, Benxi 117000, PR China;3. Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China;4. Department of Pharmacy, Liaoning Vocational College of Medicine, Shenyang 110101, PR China;1. School of Chemistry, Sun Yat-sen University, 135 Xin Gang West Road, Guangzhou 510275, PR China;2. Department of Oncology, Renmin Hospital of Wuhan University, 299 Ba Yi Road, Wuchang 430072, PR China |
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| Abstract: | Drug resistance and cancer cells metastasis have been the leading causes of chemotherapy failure and cancer-associated death in breast cancer patients. In present, various active molecules either exhibiting novel mechanism of action such as inducing autophagy or inhibiting metastasis have been developed to address these problems. However, the compounds exhibiting such dual functions have rarely been described. Previous work in our group showed that TSA, as a synthetic analog of asperphenamate, induced autophagic cell death in breast cancer cells instead of apoptosis. Furthermore, the target enzyme of TSA was predicted to be cathepin L (Cat L) by natural product consensus pharmacophore strategy. Accumulated evidences have shown that cathepsins are closely associated with migration and invasion of breast cancer cells. It seemed likely that TSA-like molecules may possess the dual functions of inducing autophagy and inhibiting metastasis. Therefore, sixty optically active derivatives were firstly designed and synthesized by replacing the A-ring moiety of TSA with other substituted-phenyl sulfonyl groups. Further cathepsin inhibitory activity assay showed that (S, S) and (S, R) isomers displayed no activity against four kinds of cathepsins (L, S, K, B), while all derivatives tested were inactive toward K and B subtypes. Compound 6a with meta-bromo substituent displayed the greatest inhibitory activity, and its inhibitory capability against Cat L and S was 3.9 and 11.5-fold more potent than that of TSA, respectively. Molecular docking also exhibited that 6a formed more hydrogen bonds or π-π contacts with Cat L or S than TSA. In order to determine whether 6a could play dual roles, its anti-cancer mechanism was further investigated. On the one hand, MDC staining experiment and western blotting analysis validated that 6a can induce autophagy in MDA-MB-231 cells. On the other hand, its metastatic inhibitory ability was also confirmed by wound healing and transwell chamber experiment. |
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| Keywords: | Cathepsin inhibitor Anti-metastatic effect Inducing autophagy Docking calculations Anti-breast cancer effects |
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