From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9.
Cell Chem Biol
; 27(1): 32-40.e3, 2020 01 16.
Article
in En
| 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Serine Proteinase Inhibitors
/
Drug Evaluation, Preclinical
/
Small Molecule Libraries
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Drug Discovery
/
Proteolysis
/
Proprotein Convertase 9
Type of study:
Diagnostic_studies
/
Screening_studies
Limits:
Humans
Language:
En
Journal:
Cell Chem Biol
Year:
2020
Document type:
Article