基于BTK抑制剂Spebrutinib设计了一类新型的氨基嘧啶基双靶向抑制剂，用于治疗急性髓系白血病。代表性化合物14d、14g、14j和14m有效抑制了BTK、FLT3和FLT3（D835Y）突变体活性，IC50低至纳摩尔级。这些化合物对白血病细胞表现出强烈的抗增殖活性，IC50为0.29-950 nM。特别是，14m对所有癌细胞系的IC50值比Spebrutinib低101-1045倍。化合物14m以剂量依赖的方式通过调节相关蛋白在MV-4-11细胞中有效诱导自噬和凋亡。最后，20 mg/kg的14m腹腔注射显著抑制了MV-4-11细胞的生长，TGI值达到95.68％，没有明显毒性。这些BTK/FLT3双靶向抑制剂为进一步的结构优化和抗肿瘤机制研究提供了有希望的前导化合物。版权所有©2023 Elsevier Inc.。保留所有权利。

A novel class of aminopyrimidine-based Bruton's tyrosine kinase (BTK) and FMS-like tyrosine kinase 3 (FLT3) dual-target inhibitors based on the BTK inhibitor spebrutinib was designed for the treatment of acute myeloid leukemia. Representative compounds 14d, 14g, 14j and 14m effectively inhibited BTK, FLT3, and FLT3(D835Y) mutant activities with low nanomolar IC50's. These compounds displayed potent antiproliferative activities against leukemia cells with IC50's of 0.29-950 nM. In particular, 14m had IC50 values 101-1045 times lower than those of spebrutinib against all cancer cell lines tested. Compound 14m effectively induced autophagy and apoptosis in MV-4-11 cells through regulating related proteins in a dose-dependent manner. Finally, intraperitoneal administration of 14m at 20 mg/kg significantly repressed the growth of MV-4-11 cells with a TGI value of 95.68% with no apparent toxicity. These BTK/FLT3 dual-target inhibitors represent promising leads for further structural optimization and antitumor mechanism studies.Copyright © 2023 Elsevier Inc. All rights reserved.