RESUMEN
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.
Asunto(s)
Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Proproteína Convertasa 9/metabolismo , Proteolisis/efectos de los fármacos , Inhibidores de Serina Proteinasa/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Inhibidores de Serina Proteinasa/química , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
Herein we report the discovery and hit-to-lead optimization of a series of spirocyclic piperidine aldosterone synthase (CYP11B2) inhibitors. Compounds from this series display potent CYP11B2 inhibition, good selectivity versus related CYP enzymes, and lead-like physical and pharmacokinetic properties.