Abstract
We report herein the discovery of a class of potent small-molecule inhibitors of anaplastic lymphoma kinase (ALK) containing a fused indoloquinoline scaffold. The most promising compound CJ-2360 has an IC50 value of 2.2 nM against wild-type ALK and low-nanomolar potency against several clinically reported ALK mutants. This compound is capable of achieving complete tumor regression in the ALK-positive KARPAS-299 xenograft model with oral administration in mice. CJ-2360 represents a promising ALK inhibitor for advanced preclinical development.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Anaplastic Lymphoma Kinase / antagonists & inhibitors*
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Apoptosis
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Cell Proliferation
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Disease Progression
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Drug Discovery*
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Female
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Humans
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Lymphoma, Large-Cell, Anaplastic / drug therapy*
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Lymphoma, Large-Cell, Anaplastic / enzymology
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Lymphoma, Large-Cell, Anaplastic / pathology
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Mice
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Mice, SCID
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Structure-Activity Relationship
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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ALK protein, human
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Anaplastic Lymphoma Kinase