Design, synthesis and biological evaluation of indolin-2-one-based derivatives as potent, selective and efficacious inhibitors of FMS-like tyrosine kinase3 (FLT3).
Activating mutations of FMS-like tyrosine kinase 3 (FLT3) are present in approximately one third of acute myeloid leukemia (AML) patients, which has been proposed as a promising drug target for AML therapy. A series of indolin-2-one derivatives bearing different groups at the solvent interface position based on sunitinib as FLT3 inhibitors were designed, synthesized and evaluated in FLT3-dependent human AML cell line MV4-11. Structure-activity relationship (SAR)analysis showed that heterocyclic alkane at the solvent interface position could significantly increase the potency for the inhibition of proliferation of MV4-11 cell line. Compound 10a and 10d exhibited better efficacy (MV4-11, IC50: 14.7 nM for 10a and 24.8 nM for 10d) than positive control sunitinib (MV4-11, IC50: 38.5 nM). The kinase and cellular inhibition assay exhibited that 10d (FLT3, IC50: 5.3 nM) was a potent and selective FLT3 inhibitor. Furthermore, the pharmacokinetic experiments showed that 10d had good properties of oral bioavailability, Cmax, Tmax, T1/2 and AUC in mice, respectively. The in vivo study indicated that 10d could significantly suppress tumor growth in MV4-11 xenografts nude mice model and occupied with a commendable therapeutic window compared to sunitinib.
['Ma|Fei|F|', 'Liu|Peng|P|', 'Lei|Min|M|', 'Liu|Jian|J|', 'Wang|Hongtao|H|', 'Zhao|Shaohua|S|', 'Hu|Lihong|L|']
D000818:Animals D045744:Cell Line, Tumor D049109:Cell Proliferation D060326:Chemistry Techniques, Synthetic D015195:Drug Design D006801:Humans D007211:Indoles D051379:Mice D047428:Protein Kinase Inhibitors D013329:Structure-Activity Relationship D023041:Xenograft Model Antitumor Assays D051941:fms-Like Tyrosine Kinase 3
Acute myeloid leukemia (AML) Indolin-2-one derivatives FLT3 inhibitors In vivo study Structure-activity relationships (SARs)