Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 127, Issue -, Pages 72-86Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.12.038
Keywords
Indolin-2-one derivatives; FLT3 inhibitors; Structure -activity relationships (SARs); Acute myeloid leukemia (AML); In vivo study
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Funding
- National Natural Science Foundation of China [81473110, 81273397, 81561148011]
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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. (C) 2016 Published by Elsevier Masson SAS.
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