用于克服T315I突变的Bcr-Abl PROTACs的设计、合成及生物学评价
Design, synthesis, and biological evaluation of Bcr-Abl PROTACs to overcome T315I mutation.
作者信息
Jiang Liang, Wang Yuting, Li Qian, Tu Zhengchao, Zhu Sihua, Tu Sanfang, Zhang Zhang, Ding Ke, Lu Xiaoyun
机构信息
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of China, School of Pharmacy, Jinan University, Guangzhou 510632, China.
Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
出版信息
Acta Pharm Sin B. 2021 May;11(5):1315-1328. doi: 10.1016/j.apsb.2020.11.009. Epub 2020 Nov 20.
Bcr-Abl threonine 315 to isoleucine 315 (T315I) gatekeeper mutation induced drug resistance remains an unmet clinical challenge for the treatment of chronic myeloid leukemia (CML). Chemical degradation of Bcr-Abl protein has become a potential strategy to overcome drug resistance. Herein, we first described the design, synthesis, and evaluation of a new class of selective Bcr-Abl proteolysis-targeting chimeric (PROTAC) degraders based on GZD824 (reported as Bcr-Abl inhibitor by our group). One of the degrader with 6-member carbon chain linkage with pomalidomide exhibits the most potent degradation efficacy with DR of 69.89% and 94.23% at 100 and 300 nmol/L, respectively, and has an IC value of 26.8 ± 9.7 nmol/L against Ba/F3 cells. Further, also displays substantial tumor regression against Ba/F3-Bcr-Abl xenograft model .
Bcr-Abl苏氨酸315突变为异亮氨酸315（T315I）的守门人突变导致的耐药性仍是慢性粒细胞白血病（CML）治疗中尚未解决的临床挑战。Bcr-Abl蛋白的化学降解已成为克服耐药性的一种潜在策略。在此，我们首次描述了基于GZD824（由我们团队报道为Bcr-Abl抑制剂）的一类新型选择性Bcr-Abl蛋白酶靶向嵌合体（PROTAC）降解剂的设计、合成和评估。其中一种与泊马度胺通过6元碳链连接的降解剂表现出最有效的降解效果，在100和300 nmol/L时的降解率分别为69.89%和94.23%，对Ba/F3细胞的IC值为26.8±9.7 nmol/L。此外，其对Ba/F3-Bcr-Abl异种移植模型也显示出显著的肿瘤消退。
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