Developing potent BTKC481S PROTACs for ibrutinib-resistant malignant lymphoma |
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| Affiliation: | 1. MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing 100084, China;2. Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China;3. Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China;1. Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China;2. School of Pharmacy, Hubei Engineering Research Center of Traditional Chinese Medicine of South Hubei Province, Hubei University of Science and Technology, Xianning 437100, China;1. Medical Research Center, The Third People''s Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu 610031, China;2. State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China |
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| Abstract: | Ibrutinib is a first-line treatment drug for B-cell malignancies. However, resistance to ibrutinib has been reported due to BTKC481S mutation. Although PROTAC strategy is expected to overcome this clinical resistance, it has limitations such as large molecular weight and moderate bioactivity, which restrict its potential clinical application. Herein, we report a new type of potent BTKC481S-targeting PROTAC degrader. Through design, computer-assisted optimization and SAR studies, we have developed a representative BTKC481S degrader L6 with a much smaller molecular weight and improved solubility. Notably, L6 demonstrates better BTK degrading activity and lower IC50 value in ibrutinib-resistant cell line than the first-generation BTK degrader P13I. Optimization strategy of L6 provides a general approach in the development of PROTACs targeting BTK and other proteins for future study. |
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