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

ABSTRACT: 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^T315I 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^T315I proteolysis-targeting chimeric (PROTAC) degraders based on GZD824 (reported as Bcr-Abl^T315I 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/F3^T315I cells. Further, 7o also displays substantial tumor regression against Ba/F3-Bcr-Abl^T315I xenograft model in vivo.

SUBMITTER: Jiang L

PROVIDER: S-EPMC8148061 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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

Jiang Liang L Wang Yuting Y Li Qian Q Tu Zhengchao Z Zhu Sihua S Tu Sanfang S Zhang Zhang Z Ding Ke K Lu Xiaoyun X

Acta pharmaceutica Sinica. B 20201120 5

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-Ab ...[more]

PMID: 34094836

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