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.

ALL, acute lymphoblastic leukemia; CML; CML, chronic myeloid leukemia; CRBN, cereblon; Clinical resistance; Co-IP, co-immunoprecipitation; DR, degradation rate; Degradation; IC50, cellular inhibition; LSCs, leukemic stem cells; NMPA, National Medical Products Administration; PROTAC; PROTAC, proteolysis-targeting chimeric; Ph+, Philadelphia chromosome; T315I mutation; T315I, threonine 315 to isoleucine 315; TGI, tumor growth inhibition; VHL, von Hippel-Lindau; cIAP1, cellular inhibitor of apoptosis protein 1.