Abstract
Vps34 (the human class III phosphoinositide 3-kinase) is a lipid kinase involved in vesicle trafficking and autophagy and therefore constitutes an interesting target for cancer treatment. Because of the lack of specific Vps34 kinase inhibitors, we aimed to identify such compounds to further validate the role of this lipid kinase in cancer maintenance and progression. Herein, we report the discovery of a series of tetrahydropyrimidopyrimidinone derivatives. Starting with hit compound 1a, medicinal chemistry optimization led to compound 31. This molecule displays potent activity, an exquisite selectivity for Vps34 with excellent properties. The X-ray crystal structure of compound 31 in human Vps34 illustrates how the unique molecular features of the morpholine synthon bestows selectivity against class I PI3Ks. This molecule exhibits suitable in vivo mouse PK parameters and induces a sustained inhibition of Vps34 upon acute administration. Compound 31 constitutes an optimized Vps34 inhibitor that could be used to investigate human cancer biology.
MeSH terms
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Amino Acid Sequence
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology*
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Area Under Curve
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Bridged Bicyclo Compounds, Heterocyclic / chemistry
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Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
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Caco-2 Cells
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Cell Line, Tumor
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Class III Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
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Class III Phosphatidylinositol 3-Kinases / chemistry
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Class III Phosphatidylinositol 3-Kinases / metabolism
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Crystallography, X-Ray
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Drug Discovery
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology*
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HeLa Cells
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Humans
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Male
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Mice, SCID
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Models, Chemical
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Models, Molecular
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Molecular Sequence Data
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Molecular Structure
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Neoplasms / drug therapy*
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Neoplasms / pathology
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Protein Binding
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Protein Structure, Tertiary
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Pyrimidinones / chemistry
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Pyrimidinones / pharmacokinetics
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Pyrimidinones / pharmacology*
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Rats, Sprague-Dawley
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Sequence Homology, Amino Acid
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Thermodynamics
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Xenograft Model Antitumor Assays
Substances
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8-(3-methylmorpholin-4-yl)-1-(3-methyl-2-oxobutyl)-2-(trifluoromethyl)-3,4-dihydro-2H-pyrimido(1,2-a)pyrimidin-6-one
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Antineoplastic Agents
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Bridged Bicyclo Compounds, Heterocyclic
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Enzyme Inhibitors
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Pyrimidinones
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Class III Phosphatidylinositol 3-Kinases
Associated data
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PDB/4UWF
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PDB/4UWG
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PDB/4UWH
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PDB/4UWK
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PDB/4UWL