title: Design, synthesis and biological evaluation of indolin-2-one-based derivatives as potent, selective and efficacious inhibitors of FMS-like tyrosine kinase3 (FLT3).
abstract: 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, T1/2and 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.
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Ma
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China.
authors.forename: Min
authors.initials: M
authors.lastname: Lei
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, Jiangsu, 200237, China. Electronic address: liujian623@njucm.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Shijiazhuang Yiling Pharmceutical Company, 238 Tianshan Street, Shijiazhuang, 050035, China.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Shijiazhuang Yiling Pharmceutical Company, 238 Tianshan Street, Shijiazhuang, 050035, China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China; School of Pharmacy, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, Jiangsu, 200237, China. Electronic address: lhhu@simm.ac.cn.
authors.forename: Lihong
authors.initials: L
authors.lastname: Hu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; C456900:indolin-2-one; D051941:fms-Like Tyrosine Kinase 3
keywords: Acute myeloid leukemia (AML); FLT3 inhibitors; Indolin-2-one derivatives; In vivo study; Structure-activity relationships (SARs)