Biological properties and structural study of new aminoalkyl derivatives of benzimidazole and benzotriazole,dual inhibitors of CK2 and PIM1 kinases |
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| Institution: | 1. Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland;2. Department für Chemie, Institut für Biochemie, Universtät zu Köln, Zülpicher Straße 47, D-50674 Köln, Germany;1. Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Boston, USA;2. Structure and Biophysics, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Boston, USA;3. 35 Gatehouse Drive, Waltham, MA 02451, USA;3. San Diego Heart Research Institute, San Diego State University, San Diego, California 92182,;4. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, and;5. Sharp Memorial Hospital, San Diego, California 92123;1. IDD Medicinal Chemistry, Sanofi Genzyme, 153 Second Avenue, Waltham MA 02451, USA;2. Oncology Biochemistry/Biology, Sanofi Genzyme, 270 Albany Street, Cambridge, MA 02139, USA;3. IDD In Vitro Biology, Sanofi, 153 Second Avenue, Waltham MA 02451, USA;4. Program Management, Sanofi Genzyme, 49 New York Avenue, Framingham MA 01701, USA;1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, People''s Republic of China;2. Department of Immunology, School of Basic Medical Science, Tianjing Medical University, People''s Republic of China |
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| Abstract: | The new aminoalkyl-substituted derivatives of known CK2 inhibitors 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi) and 4,5,6,7-tetrabromo-1H-benzotriazole (TBBt) were synthesized, and their influence on the activity of recombinant human CK2 α, CK2 holoenzyme and PIM1 kinases was evaluated. All derivatives inhibited the activity of studied kinases and the most efficient were aminopropyl-derivatives 8b and 14b. These compounds also exerted inhibition of cancer cell lines – CCRF-CEM (acute lymphoblastoid leukemia), MCF-7 (human breast cancer), and PC-3 (prostate cancer) proliferation and their EC50 is comparable with the value for clinically studied CK2 inhibitor CX-4945. Preliminary structure activity relationship analysis indicated that the spacer length affected antitumor potency, and two to three methylene units were more favorable. The complex of CK2 α1-335/8b was crystallized, both under high-salt conditions and under low-salt conditions giving crystals which diffracted X-rays to about 2.4 Å resolution, what enabled the determination of the corresponding 3D-structures. |
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| Keywords: | Casein kinase 2 CK2 Protein kinase PIM1 ATP-competitive inhibitors Antiproliferative activity Structural study |
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