Discovery of 5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazin-2(1H)-one derivatives as new potent PB2 inhibitors |
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| Institution: | 1. Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China;2. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China;3. Department of Clinical Medicine, School of Medicine, Nankai University, Tianjin 300071, China;1. Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK;2. AstraZeneca R&D Charnwood, Loughborough, UK;1. MTA-DE Homogeneous Catalysis and Reaction Mechanisms Research Group, H-4010 Debrecen, POB 7, Hungary;2. Department of Organic Chemistry, University of Debrecen, H-4010 Debrecen, POB 20, Hungary;3. Department of Physical Chemistry, University of Debrecen, H-4010 Debrecen, POB 7, Hungary;1. State Key Laboratory of Biotherapy and Cancer Center, Department of Orthopedics, West China Hospital, Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, China;2. Key Laboratory of Birth Defects and Related Diseases of Women and Children, West China Second University Hospital, Sichuan University, Chengdu, 610041, China;3. Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu, 610064, China;4. Chengdu Synguider Technology Co., Ltd., Chengdu, 610041, China;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. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China;2. Department of Thyroid and Breast Surgery, West China Hospital of Sichuan University, Chengdu, China;3. Department of Ultrasonic Medicine, West China Second Hospital, Sichuan University, Chengdu, China;4. Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu, China;5. School of Pharmacy, Chengdu University of TCM, The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicine, State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, China |
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| Abstract: | PB2 is an important subunit of influenza RNA-dependent RNA polymerase (RdRP) and has been recognized as a promising target for the treatment of influenza. We herein report the discovery of a new series of PB2 inhibitors containing the skeleton 5-(5-fluoro-1H-pyrrolo2,3-b]pyridin-3-yl)pyrazin-2(1H)-one. Compound 12b is the most potent one, which showed KD values of 0.11 μM and 0.19 μM in surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) assays, respectively. In antiviral activity and cellular cytotoxicity assays, compound 12b showed an EC50 value of 1.025 μM and a CC50 value greater than 100 μM. Molecular docking was also used to predict the binding mode of 12b with PB2. Collectively, this study provides a promising lead compound for subsequent anti-influenza drug discovery targeting PB2. |
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| Keywords: | PB2 Influenza A virus Small molecule inhibitor Structure-activity relationship |
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