Abstract
Starting from our previously developed c-KIT kinase inhibitor CHMFL-KIT-8140, through a type II kinase inhibitor binding element hybrid design approach, we discovered a novel c-KIT kinase inhibitor compound 18 (CHMFL-KIT-64), which is potent against c-KIT wt and a broad spectrum of drug-resistant mutants with improved bioavailability. 18 exhibits single-digit nM potency against c-KIT kinase and c-KIT T670I mutants in the biochemical assay and displays great potencies against most of the gain-of-function mutations in the juxtamembrane domain, drug-resistant mutations in the ATP binding pocket (except V654A), and activation loops (except D816V). In addition, 18 exhibits a good in vivo pharmacokinetic (PK) profile in different species including mice, rats, and dogs. It also displays good in vivo antitumor efficacy in the c-KIT T670I, D820G, and Y823D mutant-mediated mice models as well as in the c-KIT wt patient primary cells which are known to be imatinib-resistant. The potent activity against a broad spectrum of clinically important c-KIT mutants combining the good in vivo PK/pharmacodynamic properties of 18 indicates that it might be a new potential therapeutic candidate for gastrointestinal stromal tumors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / therapeutic use*
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Benzeneacetamides / chemical synthesis
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Benzeneacetamides / metabolism
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Benzeneacetamides / pharmacokinetics
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Benzeneacetamides / therapeutic use*
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Cell Proliferation / drug effects
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Dogs
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Drug Discovery
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Female
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Gastrointestinal Neoplasms / drug therapy
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Gastrointestinal Stromal Tumors / drug therapy*
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Humans
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Male
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Mice, Inbred BALB C
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Models, Molecular
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Molecular Structure
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Mutation
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Protein Binding
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / therapeutic use*
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Proto-Oncogene Proteins c-kit / antagonists & inhibitors*
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Proto-Oncogene Proteins c-kit / genetics
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Proto-Oncogene Proteins c-kit / metabolism
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Quinolines / chemical synthesis
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Quinolines / metabolism
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Quinolines / pharmacokinetics
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Quinolines / therapeutic use*
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Benzeneacetamides
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Protein Kinase Inhibitors
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Quinolines
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KIT protein, human
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Proto-Oncogene Proteins c-kit