Design,synthesis and biological evaluation of Proteolysis Targeting Chimeras (PROTACs) as a BTK degraders with improved pharmacokinetic properties |
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| Affiliation: | 1. International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of China, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China;2. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China;1. Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom;2. Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom;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. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China;2. Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, 610052, China;3. Hinova Pharmaceuticals Inc, 4th Floor, Building RongYao A, No. 5, Keyuan South Road, Chengdu, 610041, 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 |
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| Abstract: | A new series of Proteolysis Targeting Chimeras (PROTACs) targeting Bruton's Tyrosine Kinase (BTK) was synthesized, with the goal of improving the pharmacokinetic properties of our previously reported PROTAC, MT802. We recently described the ability of MT802 to induce degradation of both wild-type and C481S mutant BTK in immortalized cells and patient-derived B-lymphocytes. However, the pharmacokinetic properties of MT802 were not suitable for further in vivo development. Therefore, we undertook a systematic medicinal chemistry campaign to overcome this issue and made a series of PROTACs with structural modifications to the linker and E3-recruiting ligand; more specifically, the new PROTACs were synthesized with different von Hippel-Lindau (VHL) and cereblon (CRBN) ligands while keeping the BTK ligand and linker length constant. This approach resulted in an equally potent PROTAC, SJF620, with a significantly better pharmacokinetic profile than MT802. This compound may hold promise for further in vivo exploration of BTK degradation. |
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| Keywords: | PROTACs Pharmacokinetics Target protein degradation BTK CRBN VHL |
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