Discovery of novel small molecule induced selective degradation of the bromodomain and extra-terminal (BET) bromodomain protein BRD4 and BRD2 with cellular potencies |
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| Affiliation: | 1. School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China;2. State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China;3. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, PR China;4. Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, PR China;1. School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, University town, Waihuan Rd., Panyu, Guangzhou, 510006, China;2. Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China;3. School of Pharmaceutical Sciences, South-Central University for nationalities, Wuhan, 430074, China;4. Department of Pharmaceutical Production Center ＆TCM and Ethnomedicine Development International Laboratory, The First Hospital of Hunan University of Chinese Medicine, 95, Shaoshan Rd, Changsha, Hunan, 41007, China;5. College of Forestry and Landscape Architecture, South China Agricultural University, 510642, China;6. Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, P.R. China;1. College of Science, Hunan Agricultural University, Furong Rd, Changsha, 410128, China;2. Department of Pharmaceutical Production Center, The First Affiliated Hospital of Hunan University of Chinese Medicine, 95, Shaoshan Rd, Changsha, Hunan, 41007, China;3. School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, E. 232, University Town, Waihuan Rd, Panyu, Guangzhou, 510006, China;4. Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China;1. The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China;2. Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China;3. Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, Changsha, Hunan, China;4. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China;5. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China;6. Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China;7. Department of Nuclear Medicine, XiangYa Hospital, Central South University, Changsha, Hunan, China;8. Key Laboratory of Biological Nanotechnology of National Health Commission, Changsha, Hunan, 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;1. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68022, USA;2. Department of Environmental, Agricultural and Occupational Health, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska 68022, USA;3. Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68022, USA;4. Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68022, USA |
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| Abstract: | The BET proteins BRD2, BRD3, and BRD4 play important roles in transcriptional regulation and can be degraded by proteolysis-targeting chimeras (PROTACs) for BET proteins. However, the lack of intra-BET proteins selectivity limits the scope of current degraders as probes for target validation and could lead to unwanted side effects or toxicity in a therapeutic setting. We describe herein the design, synthesis, and evaluation of PROTAC BET degraders, based on the BET inhibitor with selectivity for the first Bromodomain benzo[cd]indole-2-one, alkylamide linker and cereblon ligand thalidomide. Compound 15 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4 and BRD2 over BRD3, which not only effectively inhibits cell growth in human acute leukemia cell lines, but also very effective in inhibiting solid tumors with low cytotoxic effect in the cell profiles of NCI 60 cell lines. Remarkable dependency on linker length was observed for BRD4-degrading and c-Myc-driven antiproliferative activities in acute myeloid leukemia cell line MV4-11. The small-molecular 15 represents a novel, potent, and selective class of BRD4 and BRD2 degraders for the development of therapeutics to treat cancers. |
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| Keywords: | BRD4 and BRD2 PROTAC degraders Selectivity Cancers |
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