Bcr-Abl threonine 315 to isoleucine 315(T315 I)gatekeeper mutation induced drug resistance remains an unmet clinical challenge for the treatment of chronic myeloid leukemia(CML).Chemical degradation of Bcr-AblT315 Ipr...Bcr-Abl threonine 315 to isoleucine 315(T315 I)gatekeeper mutation induced drug resistance remains an unmet clinical challenge for the treatment of chronic myeloid leukemia(CML).Chemical degradation of Bcr-AblT315 Iprotein 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-AblT315 I proteolysis-targeting chimeric(PROTAC)degraders based on GZD824(reported as Bcr-AblT315 Iinhibitor by our group).One of the degrader 7 o 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/F3T315 Icells.Further,7 o also displays substantial tumor regression against Ba/F3-Bcr-AblT315 Ixenograft model in vivo.展开更多
基金supported by National Natural Science Foundation of China(81922062 and 81874285)the National Key Research and Development Program of China(2018YFE0105800 and SQ2019YFE010401)+2 种基金National Science&Technology Major Project Key New Drug Creation and Manufacturing Program(2018ZX09711002-011-020,China)Guangdong Provincial Science and Technology Program(2018A050506043,China)Jinan University。
文摘Bcr-Abl threonine 315 to isoleucine 315(T315 I)gatekeeper mutation induced drug resistance remains an unmet clinical challenge for the treatment of chronic myeloid leukemia(CML).Chemical degradation of Bcr-AblT315 Iprotein 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-AblT315 I proteolysis-targeting chimeric(PROTAC)degraders based on GZD824(reported as Bcr-AblT315 Iinhibitor by our group).One of the degrader 7 o 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/F3T315 Icells.Further,7 o also displays substantial tumor regression against Ba/F3-Bcr-AblT315 Ixenograft model in vivo.
