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

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. (C) 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Automated summary

A new class of selective Bcr-Abl(T315I) proteolysis-targeting chimeric degraders were designed, synthesized, and evaluated, with 7o exhibiting the most potent degradation efficacy and significant tumor regression in cell and animal models.