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: 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)
• 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

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)