Discovery of a new class of PROTAC BRD4 degraders based on a dihydroquinazolinone derivative and lenalidomide/pomalidomide |
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| Affiliation: | 1. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China;2. Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China;1. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China;2. Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China;1. Department of Medicinal Chemistry, School of Pharmacy, Xi′an Jiaotong University, Xi′an, Shaanxi, 710061, PR China;2. School of Science, Xi′an Jiaotong University, Xi’an, Shaanxi, 710049, PR China;3. Instrumental Analysis Center of Xi’an Jiaotong University, Xi’an, Shaanxi, 710049, PR China;1. Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;2. Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China;1. College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China;2. Center for Molecular Medicine, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang 310032, 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;1. Institute of Chemical Industry of Forest Products, Chinese Academy of Forest, Nanjing 210042, Jiangsu, PR China;2. National Engineering Laboratory for Rice and By-products Processing, Food Science and Engineering College, Central South University of Forestry and Technology, Changsha 410004, Hunan, PR China;3. Novosibirsk Institute of Organic Chemistry, Acad. Lavrentyev ave. 9, Novosibirsk 630090, Russia;4. Institute of Tropical Medicine & the Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 501405, PR China;5. School of Computer Science and Engineering, Hunan University, Changsha 410012, PR China |
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| Abstract: | BRD4 has emerged as an attractive target for anticancer therapy. However, BRD4 inhibitors treatment leads to BRD4 protein accumulation, together with the reversible nature of inhibitors binding to BRD4, which may limit the efficacy of BRD4 inhibitors. To address these problems, a protein degradation strategy based on the proteolysis targeting chimera (PROTAC) technology has been developed to target BRD4 recently. Herein, we present our design, synthesis and biological evaluation of a new class of PROTAC BRD4 degraders, which were based on a potent dihydroquinazolinone-based BRD4 inhibitor compound 6 and lenalidomide/pomalidomide as ligand for E3 ligase cereblon. Gratifyingly, several compounds showed excellent inhibitory activity against BRD4, and high anti-proliferative potency against human monocyte lymphoma cell line THP-1. Especially, compound 21 (BRD4 BD1, IC50 = 41.8 nM) achieved a submicromolar IC50 value of 0.81 μM in inhibiting the growth of THP-1 cell line, and was 4 times more potent than compound 6. Moreover, the mechanism study established that 21 could effectively induce the degradation of BRD4 protein and suppression of c-Myc. All of these results suggested that 21 was an efficacious BRD4 degrader for further investigation. |
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| Keywords: | BRD4 degraders PROTAC Protein degradation Dihydroquinazolinone |
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