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.
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Authors | Ajit Dhananjay Jagtap, Pei-Teh Chang, Jia-Rong Liu, Hsiao-Chun Wang, Nagendra B Kondekar, Li-Jiuan Shen, Hsiang-Wen Tseng, Grace Shiahuy Chen, Ji-Wang Chern |
Journal | European journal of medicinal chemistry
(Eur J Med Chem)
Vol. 85
Pg. 268-88
(Oct 06 2014)
ISSN: 1768-3254 [Electronic] France |
PMID | 25089810
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2014 Elsevier Masson SAS. All rights reserved. |
Chemical References |
- Antineoplastic Agents
- Indoles
- Protein Kinase Inhibitors
- indolin-2-one
- fms-Like Tyrosine Kinase 3
- Aurora Kinase B
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Topics |
- Animals
- Antineoplastic Agents
(chemical synthesis, chemistry, pharmacology, therapeutic use)
- Aurora Kinase B
(antagonists & inhibitors)
- Cell Line, Tumor
- Chlorocebus aethiops
- Drug Design
- Humans
- Indoles
(chemical synthesis, chemistry, pharmacology, therapeutic use)
- Leukemia, Myeloid, Acute
(drug therapy)
- Male
- Mice
- Protein Kinase Inhibitors
(chemical synthesis, chemistry, pharmacology, therapeutic use)
- Vero Cells
- Xenograft Model Antitumor Assays
- fms-Like Tyrosine Kinase 3
(antagonists & inhibitors)
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