An exploration of solvent-front region high affinity moiety leading to novel potent ALK & ROS1 dual inhibitors with mutant-combating effects |
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| Institution: | 1. Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China;2. Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China;1. Department of Chemistry, American University, Washington, DC 20016, USA;2. Tuberculosis Research Section, LCIM, NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892, USA;3. Department of Microbiology and Immunology, Midwestern University, Chicago, IL 60515, USA;4. Department of Biochemistry, Midwestern University, Chicago, IL 60515, USA;5. Naval Research Laboratory, Code 6930 4555 Overlook Ave., Washington, DC 20375, USA;1. Laboratory for Medicinal Chemistry, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni, Shizuoka 410-2321, Japan;2. Laboratory for Pharmacology, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni, Shizuoka 410-2321, Japan;1. CAS Key Laboratory of Receptor Research and the State Key Laboratory for Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China;2. Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, 201203, China;3. University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, China;4. School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China;1. Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, United States;2. Harvard Medical School, Boston, MA 02115, United States;3. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, United States;4. Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States;5. Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, United States;6. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States;7. New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea;8. Department of Medicine, Brigham and Women''s Hospital, Boston, MA 02115, United States;1. Peter MacCallum Cancer Centre and the University of Melbourne, Melbourne, Australia;2. Massachusetts General Hospital Cancer Center, Boston, Massachusetts;3. Loxo Oncology, Inc., Stamford, Connecticut;4. Dana Farber Cancer Institute, Boston, Massachusetts;5. Luzerner Kantonsspital, Luzern, Switzerland;6. Memorial Sloan Kettering Cancer Center, New York, New York;7. University of Texas MD Anderson Cancer Center, Houston, Texas;8. Array BioPharma, Boulder, Colorado;9. Eli Lilly & Company, Indianapolis, Indiana;10. Kolling Institute of Endocrinology, Royal North Shore Hospital, and the University of Sydney, Sydney, Australia;1. High Magnetic Field Laboratory, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, PR China;2. CHMFL-HCMTC Target Therapy Joint Laboratory, 350 Shushanhu Road, Hefei, Anhui 230031, PR China;3. University of Science and Technology of China, Hefei, Anhui 230026, PR China;4. School of Life Sciences, Anhui Agricultural University, Hefei, Anhui 230036, PR China;5. Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230088, PR China;6. Hefei Cosource Medicine Technology Co. LTD., 358 Ganquan Road, Hefei, Anhui 230031, PR China |
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| Abstract: | The pyrimidine-2,4-diamine analogs exerted excellent activities in down-regulation of ALK phosphorylation. However, the prevalent drug-resistant site-mutation has gradually prevented the agents from being widely used. Herein, we conducted an exploration of high affinity moiety that bound to the solvent-front region (G1202R located) within the ATP binding site of ALK leading to the synthesis of thirty-five pyrimidine-2,4-diamine derivatives. Among these compounds, urea group was extensively derivatized which finally resulted in the identification of the ‘semi-free urea’ compound 39. All compounds were assayed cytotoxicity and enzymatic activities and 39 turned out to be the most potent one with IC50 values of 2.1, 0.91, 4.3 and 0.73 nM towards ALKwt, ALKL1196M, ALKG1202R and ROS1, respectively. The performances of 39 on ALK- & ROS1-dependent cell lines were in good accordance with enzymatic activities with IC50 values below 0.06 µM. Besides, 39 induced cell apoptosis in a dose-dependent manner in H2228 cells. Finally, the binding models of 39 with ALKwt, ROS1, ALKL1196M and ALKG1202R were ideally established which further clearly elucidated their mode of action within the active site. |
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| Keywords: | Pyrimidine-2 4-Diamine Solvent front ALK & ROS1 inhibitors Mutation-combating Apoptosis-inducing |
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