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Discovery of quinoline-based irreversible BTK inhibitors
Institution:1. Acerta Pharma B.V., Kloosterstraat 9, 5349 AB Oss, the Netherlands;2. Acerta Pharma LLC, 1549 Industrial Road, San Carlos, CA 94070, United States;1. Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China;2. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;3. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China;4. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China;5. School of Pharmacy, Nanchang University, 461 Bayi Road, Nanchang 330006, China;1. Biogen Inc., 225 Binney Street, Cambridge, MA 02142, United States;2. Sunesis Pharmaceuticals, Inc., 395 Oyster Point Boulevard, South San Francisco, CA 94080, United States;1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, Jinan 250012, PR China;2. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;3. Shandong Qidu Pharmaceutical Co., Ltd., 28 Renmin East Road, Zibo 255400, PR China;1. College of Pharmacy, Dalian Medical University, Dalian 116044, PR China;2. Department of Respiratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China;1. College of Pharmacy, Dalian Medical University, Dalian 116044, PR China;2. Department of Respiratory Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China
Abstract:Bruton tyrosine kinase (BTK) is an important target in oncology and (auto)immunity. Various BTK inhibitors have been approved or are currently in clinical development. A novel BTK inhibitor series was developed starting with a quinazoline core. Moving from a quinazoline to a quinoline core provided a handle for selectivity for BTK over EGFR and resulted in the identification of potent and selective BTK inhibitors with good potency in human whole blood assay. Furthermore, proof of concept of this series for BTK inhibition was shown in an in vivo mouse model using one of the compounds identified.
Keywords:BTK  Quinoline  Covalent  Irreversible  Kinases
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