Structure-based design and modular synthesis of novel PI4K class II inhibitors bearing a 4-aminoquinazoline scaffold
Language English Country Great Britain, England Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
36184029
DOI
10.1016/j.bmcl.2022.129010
PII: S0960-894X(22)00486-3
Knihovny.cz E-resources
- Keywords
- ATP-binding site, PI4K2A inhibitor, Phosphatidylinositol 4-kinase class II, Quinazoline derivative, SAR investigation,
- MeSH
- 1-Phosphatidylinositol 4-Kinase * chemistry metabolism MeSH
- Adenine MeSH
- Adenosine Triphosphate * metabolism MeSH
- Ligands MeSH
- Drug Design MeSH
- Molecular Docking Simulation MeSH
- Structure-Activity Relationship MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 1-Phosphatidylinositol 4-Kinase * MeSH
- 4-aminoquinazoline MeSH Browser
- Adenine MeSH
- Adenosine Triphosphate * MeSH
- Ligands MeSH
Novel 4-aminoquinazoline-6-carboxamide derivatives bearing differently substituted aryl or heteroaryl groups at position 7 in the core were rationally designed, synthesized and evaluated for biological activity in vitro as phosphatidylinositol 4-kinase IIα (PI4K2A) inhibitors. The straightforward approach described here enabled the sequential, modular synthesis and broad functionalization of the scaffold in a mere six steps. The SAR investigation reported here is based on detailed structural analysis of the conserved binding mode of ATP and other adenine derivatives to the catalytic site of type II PI4Ks, combined with extensive docking studies. Several compounds exhibited significant activity against PI4K2A. Moreover, we solved a crystal structure of PI4K2B in complex with one of our lead ligand candidates, which validated the ligand binding site and pose predicted by our docking-based ligand model. These discoveries suggest that our structure-based approach may be further developed and employed to synthesize new inhibitors with optimized potency and selectivity for this class of PI4Ks.
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