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.

从Bcr-Abl苏氨酸315到异亮氨酸315（T315I）关守突变诱导的耐药性仍然是治疗慢性粒细胞白血病（CML）的临床挑战。Bcr-Abl ^T315I蛋白的化学降解已成为克服耐药性的潜在策略。在本文中，我们首先描述了基于GZD824的新型一类选择性Bcr-Abl ^T315I蛋白水解靶向嵌合（PROTAC）降解剂的设计，合成和评估（我们小组将其称为Bcr-Abl ^T315I抑制剂）。具有与pomalidomide的6员碳链键合的7o降解物之一显示出最有效的降解功效，在100和300 nmol / L时的DR分别为69.89％和94.23％，并且具有IC ₅₀相对于Ba / F3 ^T315I细胞的26.8±9.7 nmol / L值。此外，7o还显示出针对体内Ba / F3-Bcr-Abl ^T315I异种移植模型的实质性肿瘤消退。