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Cell Chem Biol ; 27(1): 32-40.e3, 2020 01 16.
Article in English | MEDLINE | ID: mdl-31653597

ABSTRACT

Proprotein convertase substilisin-like/kexin type 9 (PCSK9) is a serine protease involved in a protein-protein interaction with the low-density lipoprotein (LDL) receptor that has both human genetic and clinical validation. Blocking this protein-protein interaction prevents LDL receptor degradation and thereby decreases LDL cholesterol levels. Our pursuit of small-molecule direct binders for this difficult to drug PPI target utilized affinity selection/mass spectrometry, which identified one confirmed hit compound. An X-ray crystal structure revealed that this compound was binding in an unprecedented allosteric pocket located between the catalytic and C-terminal domain. Optimization of this initial hit, using two distinct strategies, led to compounds with high binding affinity to PCSK9. Direct target engagement was demonstrated in the cell lysate with a cellular thermal shift assay. Finally, ligand-induced protein degradation was shown with a proteasome recruiting tag attached to the high-affinity allosteric ligand for PCSK9.


Subject(s)
Drug Discovery , Drug Evaluation, Preclinical , Proprotein Convertase 9/metabolism , Proteolysis/drug effects , Serine Proteinase Inhibitors/pharmacology , Small Molecule Libraries/pharmacology , Humans , Ligands , Models, Molecular , Molecular Structure , Serine Proteinase Inhibitors/chemistry , Small Molecule Libraries/chemistry
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