Abstract
Axl and Mer are members of the TAM (Tyro3-Axl-Mer) family of receptor tyrosine kinases. Previously, we reported that enzyme-mediated inhibition of Mer by an Axl/Mer dual inhibitor led to retinal toxicity in mice, whereas selective Axl inhibition by compound 1 did not. On the other hand, compound 1 showed low membrane permeability. Here, we designed and synthesized a novel series of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine derivatives and evaluated their Axl and Mer inhibitory activities, leading to identification of ER-001259851-000 as a potent and selective Axl inhibitor with drug-likeness and a promising pharmacokinetic profile in mice.
Keywords:
Axl; Cancer; Inhibitor; Mer; Small molecule; Structure-activity relationships.
Copyright © 2021 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Axl Receptor Tyrosine Kinase
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Dose-Response Relationship, Drug
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Drug Discovery*
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Humans
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Mice
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Microsomes, Liver / chemistry
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Microsomes, Liver / metabolism
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Molecular Structure
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / metabolism
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Pyridines / chemical synthesis
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Pyridines / chemistry
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Pyridines / pharmacology*
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / metabolism
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Structure-Activity Relationship
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c-Mer Tyrosine Kinase / antagonists & inhibitors*
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c-Mer Tyrosine Kinase / metabolism
Substances
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Pyridines
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Pyrimidines
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tetrahydropyrido(4,3-d)pyrimidine
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MERTK protein, human
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Receptor Protein-Tyrosine Kinases
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c-Mer Tyrosine Kinase
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Axl Receptor Tyrosine Kinase