Selective CDK6 degradation mediated by cereblon,VHL, and novel IAP-recruiting PROTACs |
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| Affiliation: | 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. 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;3. Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Kanagawa 210-9501;4. Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd., Kanagawa 251-8555, Japan;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. State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, 222 S. Tianshui Rd, Lanzhou, 730000, PR China;2. Suzhou Degen Bio-medical Co., Ltd, No.1 Huayun Road, SIP, Suzhou, 215000, PR China;3. School of Pharmacy, Lanzhou University, 222 S. Tianshui Rd, Lanzhou, 730000, PR China |
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| Abstract: | Inhibitors of CDK4 and CDK6 have emerged as important FDA-approved treatment options for breast cancer patients. The properties and pharmacology of CDK4/6 inhibitor medicines have been extensively profiled, and investigations into the degradation of these targets via a PROTAC strategy have also been reported. PROTACs are a novel class of small-molecules that offer the potential for differentiated pharmacology compared to traditional inhibitors by redirecting the cellular ubiquitin–proteasome system to degrade target proteins of interest. We report here the preparation of palbociclib-based PROTACs that incorporate binders for three different E3 ligases, including a novel IAP-binder, which effectively degrade CDK4 and CDK6 in cells. In addition, we show that the palbociclib-based PROTACs in this study that recruit different E3 ligases all exhibit preferential CDK6 vs. CDK4 degradation selectivity despite employing a selection of linkers between the target binder and the E3 ligase binder. |
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| Keywords: | CDK4 CDK6 PROTAC Palbociclib |
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