title: Novel acylureidoindolin-2-one derivatives as dual Aurora B/FLT3 inhibitors for the treatment of acute myeloid leukemia.
abstract: A series of 6-acylureido derivatives containing a 3-(pyrrol-2-ylmethylidene)indolin-2-one scaffold were synthesized as potential dual Aurora B/FLT3 inhibitors by replacing the 6-arylureido moiety in 6-arylureidoindolin-2-one-based multi-kinase inhibitors. (Z)-N-(2-(pyrrolidin-1-yl)ethyl)-5-((6-(3-(2-fluoro-4-methoxybenzoyl)ureido)-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (54) was identified as a dual Aurora B/FLT3 inhibitor (IC50 = 0.4 nM and 0.5 nM, respectively). Compound 54 also exhibited potent cytotoxicity with single-digit nanomolar IC50 values against the FLT3 mutant-associated human acute myeloid leukemia (AML) cell lines MV4-11 (FLT3-ITD) and MOLM-13 (FLT3-ITD). Compound 54 also specifically induced extrinsic apoptosis by inhibiting the phosphorylation of the Aurora B and FLT3 pathways in MOLM-13 cells. Compound 54 had a moderate pharmacokinetic profile. The mesylate salt of 54 efficiently inhibited tumor growth and reduced the mortality of BALB/c nude mice (subcutaneous xenograft model) that had been implanted with AML MOLM-13 cells. Compound 54 is more potent than sunitinib not only against FLT3-WT AML cells but also active against sunitinib-resistant FLT3-ITD AML cells. This study demonstrates the significance of dual Aurora B/FLT3 inhibitors for the development of potential agents to treat AML.
authors.affiliation: School of Pharmacy and Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, Lin Sen South Road, Taipei 10050, Taiwan.
authors.forename: Ajit Dhananjay
authors.initials: AD
authors.lastname: Jagtap
authors.affiliation: School of Pharmacy and Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, Lin Sen South Road, Taipei 10050, Taiwan.
authors.forename: Pei-Teh
authors.initials: PT
authors.lastname: Chang
authors.affiliation: School of Pharmacy and Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, Lin Sen South Road, Taipei 10050, Taiwan.
authors.forename: Jia-Rong
authors.initials: JR
authors.lastname: Liu
authors.affiliation: School of Pharmacy and Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, Lin Sen South Road, Taipei 10050, Taiwan.
authors.forename: Hsiao-Chun
authors.initials: HC
authors.lastname: Wang
authors.affiliation: School of Pharmacy and Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, Lin Sen South Road, Taipei 10050, Taiwan.
authors.forename: Nagendra B
authors.initials: NB
authors.lastname: Kondekar
authors.affiliation: School of Pharmacy and Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, Lin Sen South Road, Taipei 10050, Taiwan.
authors.forename: Li-Jiuan
authors.initials: LJ
authors.lastname: Shen
authors.affiliation: Biomedical Engineering Research Laboratories, Industrial Technology Research Institute, No. 321, Section 2, Guangfu Road, Hsinchu 30011, Taiwan.
authors.forename: Hsiang-Wen
authors.initials: HW
authors.lastname: Tseng
authors.affiliation: Department of Applied Chemistry, Providence University, No. 200, Section 7, Taiwan Boulevard, Taichung 43301, Taiwan. Electronic address: grace@pu.edu.tw.
authors.forename: Grace Shiahuy
authors.initials: GS
authors.lastname: Chen
authors.affiliation: School of Pharmacy and Center for Innovative Therapeutics Discovery, National Taiwan University, No. 33, Lin Sen South Road, Taipei 10050, Taiwan; Department of Life Science, College of Life Science, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei 10617, Taiwan. Electronic address: jwchern@ntu.edu.tw.
authors.forename: Ji-Wang
authors.initials: JW
authors.lastname: Chern
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; C456900:indolin-2-one; D051941:fms-Like Tyrosine Kinase 3; D064107:Aurora Kinase B
keywords: Acyluriedoindolin-2-one; Aurora B; FLT-3; Inhibitors; Leukemia; Structure–activity relationship