Discovery of 1,8-disubstituted-[1,2,3]triazolo[4,5-c]quinoline derivatives as a new class of Hippo signaling pathway inhibitors |
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| Institution: | 1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China;2. Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China;1. Department of Medicinal Chemistry, Zydus Research Centre, Sarkhej-Bavla, N.H. 8A Moraiya, Ahmedabad 382210, India;2. Department of Chemistry, Faculty of Science, M.S. University of Baroda, Vadodara 390002, India;3. Department of Bioinformatics, Zydus Research Centre, Sarkhej-Bavla, N.H. 8A Moraiya, Ahmedabad 382210, India;4. Department of Pharmacology, Zydus Research Centre, Sarkhej-Bavla, N.H. 8A Moraiya, Ahmedabad 382210, India;5. Department of Cell Biology, Zydus Research Centre, Sarkhej-Bavla, N.H. 8A Moraiya, Ahmedabad 382210, India;1. Department of Medicinal Chemistry, School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China;2. 2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, 94 Weijin Road, Tianjin, 300071, China;3. State Key Laboratory of Medicinal Chemical Biology, 94 Weijin Road, Tianjin, 300071, China;4. State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin, 300071, China;5. Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China;1. State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China;2. Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Ministry of Education & State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550004, Guizhou, China;3. College of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, 453003, China;4. Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, 610052, China;1. Integral BioSciences, Pvt. Ltd., C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh, 201306, India;2. Medivation, Now Pfizer Inc., 525 Market Street, 36th Floor, San Francisco, CA 94105, United States;3. Current address: Palo Alto Pharmaceutical Consulting Service, United States |
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| Abstract: | Inhibitors of the Hippo signaling pathway have been demonstrated to have a potential clinical application in cases such as tissue repair and organ regeneration. However, there is a lack of potent Hippo pathway inhibitors at present. Herein we report the discovery of a series of 1,8-disubstituted-1,2,3]triazolo4,5-c]quinoline derivatives as a new class of Hippo pathway inhibitors by utilizing a cell line-based screening model (A549-CTGF). Structure-activity relationship (SAR) of these compounds was also discussed. The most potent compound in the A549-CTGF cell assay, 11g, was then evaluated by real-time PCR and immunofluorescence assays. Overall, this study provides a starting point for later drug discovery targeting the Hippo signaling pathway. |
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| Keywords: | Hippo signaling pathway Tissue repair and organ regeneration Small molecule inhibitor Structure-activity relationship |
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