Structure-based design and modular synthesis of novel PI4K class II inhibitors bearing a 4-aminoquinazoline scaffold

0562658 - ÚOCHB 2023 RIV GB eng J - Článek v odborném periodiku
Misehe, Mbilo - Klíma, Martin - Matoušová, Marika - Chalupská, Dominika - Dejmek, Milan - Šála, Michal - Mertlíková-Kaiserová, Helena - Bouřa, Evžen - Nencka, Radim
Structure-based design and modular synthesis of novel PI4K class II inhibitors bearing a 4-aminoquinazoline scaffold.
Bioorganic and Medicinal Chemistry Letters. Roč. 76, November (2022), č. článku 129010. ISSN 0960-894X. E-ISSN 1464-3405
Grant CEP: GA MŠMT(CZ) EF16_019/0000729; GA MZd(CZ) NU20-05-00472
Institucionální podpora: RVO:61388963
Klíčová slova: phosphatidylinositol 4-kinase class II * PI4K2A inhibitor * quinazoline derivative * SAR investigation * ATP-binding site
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 2.7, rok: 2022
Způsob publikování: Omezený přístup
https://doi.org/10.1016/j.bmcl.2022.129010

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.
Trvalý link: https://hdl.handle.net/11104/0334914


Vědecká data: PDB