Design, synthesis and pharmacological characterization of aminopyrimidine derivatives as BTK/FLT3 dual-target inhibitors against acute myeloid leukemia

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 & PRIME;s. These compounds displayed potent antiproliferative activities against leukemia cells with IC50 & PRIME;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, intraperi-toneal 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.

Automated summary

A novel class of aminopyrimidine-based dual-target inhibitors, designed for the treatment acute myeloid leukemia, effectively inhibited the activities of BTK, FLT3, and FLT3(D835Y) mutant. These compounds showed potent antiproliferative activities against leukemia cells and induced autophagy and apoptosis. In vivo studies demonstrated that compound 14m significantly suppressed the growth of MV-4-11 cells without apparent toxicity. These dual-target inhibitors hold promise for further optimization and mechanism studies.