Abstract
9-Substituted 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles were discovered as highly selective and potent anaplastic lymphoma kinase (ALK) inhibitors by structure-based drug design. The high target selectivity was achieved by introducing a substituent close to the E(0) region of the ATP binding site, which has a unique amino acid sequence. Among the identified inhibitors, compound 13d showed highly selective and potent inhibitory activity against ALK with an IC(50) value of 2.9 nM and strong antiproliferative activity against KARPAS-299 with an IC(50) value of 12.8 nM. The compound also displayed significant antitumor efficacy in an established ALK fusion gene-positive anaplastic large-cell lymphoma (ALCL) xenograft model in mice without body weight loss.
MeSH terms
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Anaplastic Lymphoma Kinase
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Carbazoles / chemical synthesis*
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Carbazoles / pharmacokinetics
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Carbazoles / pharmacology
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Cell Line, Tumor
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Drug Design
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Drug Screening Assays, Antitumor
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Female
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Humans
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In Vitro Techniques
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Macaca fascicularis
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Male
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Mice
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Mice, SCID
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Microsomes, Liver / metabolism
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Models, Molecular
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Neoplasm Transplantation
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Piperazines / chemical synthesis*
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Piperazines / pharmacokinetics
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Piperazines / pharmacology
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Structure-Activity Relationship
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Transplantation, Heterologous
Substances
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9-ethyl-6,6-dimethyl-8-(4-oxetan-3-ylpiperazin-1-yl)-11-oxo-6,11-dihydro-5H-benzo(b)carbazole-3-carbonitrile
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Antineoplastic Agents
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Carbazoles
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Piperazines
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ALK protein, human
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Alk protein, mouse
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Anaplastic Lymphoma Kinase
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Receptor Protein-Tyrosine Kinases