Discovery and Biological evaluation of pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione derivatives as potent Bruton’s tyrosine kinase inhibitors |
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| Institution: | 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. College of Pharmacy, Dalian Medical University, Dalian 116044, PR China;2. Department of Respiratory, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China;1. High Magnetic Field Laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, PR China;2. University of Science and Technology of China, Hefei, Anhui 230036, PR China;3. CHMFL-HCMTC Target Therapy Joint Laboratory, 350 Shushanhu Road, Hefei Anhui 230031, PR China;4. Department of Chemistry, University of California-Riverside, 900 University Ave., Riverside, CA 92521, USA;5. Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave., Boston, MA 02115, USA;6. Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 250 Longwood Ave, SGM 628, Boston, MA 02115, USA;7. Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230088, PR China;8. Hefei Science Center, Chinese Academy of Sciences, 350 Shushanhu Road, Hefei, Anhui, 230031, PR China;1. EMD Serono Research & Development Institute, Inc., 45A Middlesex Turnpike, Billerica 01821, MA, USA;2. Constellation Pharmaceuticals, 215 First Street, Suite 200, Cambridge, MA 02142, USA;3. F. Hoffmann-La Roche AG, Konzern-Hauptsitz, Grenzacherstrasse 124, CH-4070 Basel, Switzerland;1. Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi’an Jiaotong University, No. 76, Yanta West Road, Xi’an 710061, PR China;2. Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No. 699-18, Xuan Wu District, Nanjing 210042, PR China;3. Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China;4. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, No. 24, Tongjiaxiang, Nanjing 210009, 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 |
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| Abstract: | Aberrant activation of B cell receptor (BCR) signal transduction cascade contributes to the propagation and maintenance of B cell malignancies. The discovery of mall molecules with high potency and selectivity against Bruton’s tyrosine kinase (BTK), a key signaling molecule in this cascade, is particularly urgent in modern treatment regimens. Herein, a series of pyrimido4,5-d]pyrimidine-2,4(1H,3H)-dione derivatives were reported as potent BTK inhibitors. Compounds 17 and 18 displayed strong BTK inhibitory activities in the enzymatic inhibition assay, with the IC50 values of 1.2 and 0.8 nM, respectively, which were comparable to that of ibrutinib (IC50 = 0.6 nM). Additionally, compound 17 had a more selective profile over EGFR than ibrutinib. According to the putative binding poses, the molecular basis of this series of compounds with respect to potency against BTK and selectivity over EGFR was elucidated. In further experiments at cellular level, compounds 17 and 18 significantly inhibited the proliferation of Ramos and TMD8 cells. And they arrested 75.4% and 75.2% of TMD8 cells in G1 phase, respectively, at the concentration of 1 µM. |
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| Keywords: | Bruton’s tyrosine kinase B-cell malignancies Potent inhibitors Structure-activity relationship Cellular activities |
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