具有优化生物利用度的靶向布鲁顿酪氨酸激酶（BTK）的蛋白质靶向嵌合体（PROTAC）的设计、合成及评估
Design, synthesis, and evaluation of BTK-targeting PROTACs with optimized bioavailability and .
作者信息
Sun Yonghui, Yang Zimo, Zhang Zhimin, Li Zhen, Guo Liubin, Pan Hao, Luo Xin, Liu Dongzhou, Rao Yu
机构信息
MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University Beijing 100084 China
Global Drug Development Center, Huadong Medicine Co., Ltd No. 866 Mogan Mountain Road Hangzhou 310011 China
出版信息
RSC Med Chem. 2023 Jun 21;14(8):1562-1566. doi: 10.1039/d3md00216k. eCollection 2023 Aug 16.
Abstract
Ibrutinib is a first-line drug for the treatment of B-cell malignancies. BTK mutation has led to drug resistance during clinical application. Herein, a novel BTK-targeting PROTAC molecule with better solubility and bioavailability was developed. Compound 15-271 has better solubility than ibrutinib and some reported BTK PROTACs. 15-271 has better liver microsomal stability than its analogues in multiple species. More importantly, 15-271 has a longer half-life and better bioavailability . The development strategy of compound 15-271 can be a general procedure for the optimization of other PROTACs.
摘要
伊布替尼是治疗B细胞恶性肿瘤的一线药物。BTK突变在临床应用中导致了耐药性。在此，开发了一种具有更好溶解性和生物利用度的新型靶向BTK的PROTAC分子。化合物15-271比伊布替尼和一些已报道的BTK PROTAC具有更好的溶解性。在多个物种中，15-271比其类似物具有更好的肝微粒体稳定性。更重要的是，15-271具有更长的半衰期和更好的生物利用度。化合物15-271的开发策略可以作为优化其他PROTAC的通用程序。
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