Design, synthesis, and biological evaluation of Bcr-Abl PROTACs to overcome T315I mutation

• Main Authors: Liang Jiang (Author), Yuting Wang (Author), Qian Li (Author), Zhengchao Tu (Author), Sihua Zhu (Author), Sanfang Tu (Author), Zhang Zhang (Author), Ke Ding (Author), Xiaoyun Lu (Author)
• Format: Book
• Published: Elsevier, 2021-05-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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-AblT315I 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-AblT315I proteolysis-targeting chimeric (PROTAC) degraders based on GZD824 (reported as Bcr-AblT315I inhibitor by our group). One of the degrader 7o 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 IC50 value of 26.8 ± 9.7 nmol/L against Ba/F3T315I cells. Further, 7o also displays substantial tumor regression against Ba/F3-Bcr-AblT315I xenograft model in vivo.

Item Description

2211-3835
10.1016/j.apsb.2020.11.009