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, C_max, T_max, T_1/2 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.

Acute myeloid leukemia (AML); FLT3 inhibitors; Indolin-2-one derivatives; In vivo study; Structure-activity relationships (SARs).