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  • Novel acylureidoindolin-2-one derivatives as dual Aurora B/FLT3 inhibitors for the treatment of acute myeloid leukemia.

Novel acylureidoindolin-2-one derivatives as dual Aurora B/FLT3 inhibitors for the treatment of acute myeloid leukemia.

European journal of medicinal chemistry (2014-08-05)
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
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.

MATERIALS
Product Number
Brand
Product Description

Supelco
1-Methyl-2-pyrrolidinone, analytical standard
Sigma-Aldrich
1-Methyl-2-pyrrolidinone, puriss. p.a., ≥99.0% (GC)
Sigma-Aldrich
1-Methyl-2-pyrrolidinone, anhydrous, 99.5%
Sigma-Aldrich
1-Methyl-2-pyrrolidinone, ReagentPlus®, 99%
Sigma-Aldrich
1-Methyl-2-pyrrolidinone, suitable for HPLC, ≥99%
Sigma-Aldrich
1-Methyl-2-pyrrolidinone, biotech. grade, ≥99.7%
Sigma-Aldrich
1-Methyl-2-pyrrolidinone, ACS reagent, ≥99.0%