Structure-based drug optimization and biological evaluation of tetrahydroquinolin derivatives as selective and potent CBP bromodomain inhibitors |
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| Affiliation: | 1. Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China;2. University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China;3. Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China;4. School of Life and Technology, Harbin Institute of Technology, Harbin 150001, China;5. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA;6. Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China;7. Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China;8. Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao 266237, China;1. Key Laboratory of Molecule Synthesis and Function Discovery (Fujian Province University), College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China;2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China;3. University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China;1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China;2. University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China;3. State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China;4. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China;5. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA;6. Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA;1. Department of Chemistry, College of Sciences, Shanghai University, 99 Shangda Road, Shanghai 200444, China;2. Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China;3. CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China;4. Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China;5. University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China;6. In Vitro Biology, Shanghai ChemPartner Life Science Co., Ltd., #5 Building, 998 Halei Road, Shanghai 201203, China;1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai, 201203, China;2. Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China;3. University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China;4. School of Life Science and Medicine, Dalian University of Technology, 2 Dagong Road, Panjin, China |
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| Abstract: | CBP bromodomain could recognize acetylated lysine and function as transcription coactivator to regulate transcription and downstream gene expression. Furthermore, CBP has been shown to be related to many human malignancies including acute myeloid leukemia. Herein, we identified DC-CPin734 as a potent CBP bromodomain inhibitor with a TR-FRET IC50 value of 19.5 ± 1.1 nM and over 400-fold of selectivity against BRD4 bromodomains through structure based rational drug design guided iterative chemical modification endeavoring to discover optimal tail-substituted tetrahydroquinolin derivatives. Moreover, DC-CPin734 showed potent inhibitory activity to AML cell line MV4-11 with an IC50 value of 0.55 ± 0.04 μM, and its cellular on-target effects were further evidenced by c-Myc downregulation results. In summary, DC-CPin734 showing good potency, selectivity and anti AML activity could serve as a potent and selective in vitro and in vivo probe of CBP bromodomain and a promising lead compound for future drug development. |
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| Keywords: | Drug design CBP Bromodomain Inhibitor Acute myeloid leukemia |
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