Novel acylureidoindolin-2-one derivatives as dual Aurora B/FLT3 inhibitors for the treatment of acute myeloid leukemia
Journal
European Journal of Medicinal Chemistry
Journal Volume
85
Pages
268-288
Date Issued
2014
Author(s)
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. ? 2014 Elsevier Masson SAS. All rights reserved.
Subjects
Acyluriedoindolin-2-one; Aurora B; FLT-3; Inhibitors; Leukemia; Structure-activity relationship
SDGs
Other Subjects
2 [5 [[6 [3 (2 fluoro 4 methoxybenzoyl)ureido] 2 oxoindolin 3 ylidene]methyl] 2,4 dimethyl 1h pyrrol 3 yl]ethyl 4 methlypiperazin 1 yl ketone; 2 [5 [[6 [3 (2 fluoro 4 methoxybenzoyl)ureido] 2 oxoindolin 3 ylidene]methyl] 2,4 dimethyl 1h pyrrol 3 yl]ethyl morpholin 4 yl ketone; 3 [5 [[5 fluoro 6 [3 (2 fluoro 4 methoxybenzoyl)ureido] 2 oxoindolin 3 ylidene]methyl] 2,4 dimethyl 1h pyrrol 3 yl]propanoic acid; 3 [5 [[6 [3 (2 fluoro 4 methoxybenzoyl)ureido] 2 oxoindolin 3 ylidene]methyl] 2,4 dimethyl 1h pyrrol 3 yl]propanoic acid acid; 5 [[5 fluoro 6 [3 (2 fluoro 4 methoxybenzoyl)ureido] 2 oxoindolin 3 ylidene]methyl] 2,4 dimethyl 1h pyrrole 3carboxylic acid; 5 [[5 fluoro 6 [3 (4 methoxybenzoyl)ureido] 2 oxoindolin 3 ylidene]methyl] 2,4 dimethyl 1h pyrrole 3 carboxylic acid; 5 [[5 fluoro 6 [3 (4 methoxybenzoyl)ureido] 2 oxoindolin 3 ylidene]methyl] 2,4 dimethyl 1h pyrrole 3 propanoic acid; 5 [[6 [3 (2 fluoro 4 methoxybenzoyl)ureido] 2 oxoindolin 3 ylidene]methyl] 2,4 dimethyl 1h pyrrole 3 carboxylic acid; 5 [[6 [3 (4 methoxybenzoyl)ureido] 2 oxoindolin 3 ylidene]methyl] 2,4 dimethyl 1h pyrrole 3 carboxylic acid; antineoplastic agent; aurora kinase inhibitor; barasertib; ethyl 3 [5 [[6 [3 (2 fluoro 4 methoxybenzoyl)ureido] 2 oxoindolin 3 ylidene]methyl] 2,4 dimethyl 1h pyrrol 3 yl]propanoate; n (2 oxoindolin 4 ylcarbamoyl) 4 methoxybenzamide; n (2 oxoindolin 5 ylcarbamoyl) 4 methoxybenzamide; n (2 oxoindolin 6 ylcarbamoyl) 2 fluorobenzamide; n (2 oxoindolin 6 ylcarbamoyl) 3,4 dichlorobenzamide; n (2 oxoindolin 6 ylcarbamoyl) 3,5 dimethoxybenzamide; n (2 oxoindolin 6 ylcarbamoyl) 4 (dimethylamino)benzamide; n (2 oxoindolin 6 ylcarbamoyl) 4 (trifluoromethyl)benzamide; n (2 oxoindolin 6 ylcarbamoyl) 4 methylbenzamide; n (2 oxoindolin 7 ylcarbamoyl) 4 methoxybenzamide; n (5 fluoro 2 oxoindolin 6 ylcarbamoyl) 2 fluoro 4 methoxybenzamide; 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; n [3 (1h pyrrol 2 ylmethylidene) 2 oxoindolin 4 ylcarbamoyl] 4 methoxybenzamide; n [3 (1h pyrrol 2 ylmethylidene) 2 oxoindolin 5 ylcarbamoyl] 4 methoxybenzamide; n [3 (1h pyrrol 2 ylmethylidene) 2 oxoindolin 6 ylcarbamoyl] 4 methoxybenzamide; n [3 (1h pyrrol 2 ylmethylidene) 2 oxoindolin 7 ylcarbamoyl] 4 methoxybenzamide; unclassified drug; unindexed drug; [5 [[6 [3 (2 fluoro 4 methoxybenzoyl)ureido] 2 oxoindolin 3 ylidene]methyl] 2,4 dimethyl 1h pyrrol 3 yl]morpholin 4 yl ketone; [5 [[6 [3 (2 fluoro 4 methoxybenzoyl)ureido] 2 oxoindolin 3 ylidene]methyl] 2,4 dimethyl 1h pyrrole 3 yl] 4 methlypiperazin 1 yl ketone; antineoplastic agent; aurora B kinase; CD135 antigen; indole derivative; indolin-2-one; protein kinase inhibitor; 1 methyl 2 pyrrolidinone; aurora B kinase; aurora kinase inhibitor; CD135 antigen; indole derivative; protein tyrosine kinase inhibitor; sunitinib; ureidopenicillin derivative; acute granulocytic leukemia; aldol reaction; animal experiment; animal model; animal tissue; antineoplastic activity; apoptosis; area under the curve; article; binding affinity; cancer inhibition; cancer resistance; cell viability; controlled study; cyclization; distribution volume; drug bioavailability; drug clearance; drug conformation; drug cytotoxicity; drug efficacy; drug half life; drug mechanism; drug penetration; drug potency; drug safety; drug solubility; drug synthesis; enzyme inhibition; G2 phase cell cycle checkpoint; gastrointestinal absorption; human; human cell; hydrogen bond; hydrogenation; IC 50; in vitro study; in vivo study; lipophilicity; maximum plasma concentration; mortality; mouse; myeloid leukemia cell line; nonhuman; protein phosphorylation; single drug dose; structure activity relation; time to maximum plasma concentration; tumor volume; tumor xenograft; animal; antagonists and inhibitors; chemistry; Chlorocebus aethiops; drug design; drug screening; Leukemia, Myeloid, Acute; male; synthesis; tumor cell line; Vero cell line; acute granulocytic leukemia; Article; BALB/c nude mouse; drug identification; drug inhibition; enzyme phosphorylation; IC50; Animals; Antineoplastic Agents; Aurora Kinase B; Cell Line, Tumor; Cercopithecus aethiops; Drug Design; fms-Like Tyrosine Kinase 3; Humans; Indoles; Leukemia, Myeloid, Acute; Male; Mice; Protein Kinase Inhibitors; Vero Cells; Xenograft Model Antitumor Assays
Type
journal article