Bcr-Abl threonine 315 to isoleucine 315(T315I)gatekeeper mutation induced drug resis-tance remains an unmet clinical challenge for the treatment of chronic myeloid leukemia(CML).Chem-ical 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 inhibi-tor by our group).One of the degrader 7o with 6-member carbon chain linkage with pomalidomide ex-hibits 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 dis-plays substantial tumor regression against Ba/F3-Bcr-AblT315I xenograft model in vivo.