A Novel, Orally Bioavailable, Small-Molecule Inhibitor of PCSK9 With Significant Cholesterol-Lowering Properties In Vivo

• Published in: Journal of lipid research 2022-11, Vol.63 (11), p.100293, Article 100293
• Main Authors: Suchowerska, Alexandra K., Stokman, Geurt, Palmer, James T., Coghlan, Phillip A., Pieterman, Elsbet J., Keijzer, Nanda, Lambert, Gilles, Chemello, Kevin, Jaafar, Ali K., Parmar, Jasneet, Yan, Liping, Tong, Yingtao, Mu, Lin, Princen, Hans M.G., Bonnar, James, Evison, Benny J.
• Format: Article
• Language: English
• Subjects: Animals; Anticholesteremic Agents - pharmacology; apolipoproteins; Apolipoproteins E; cardiovascular disease; Cholesterol; Cholesterol, LDL; drug therapy; Humans; hypercholesterolemia; Hyperlipidemias - drug therapy; LDL; Life Sciences; lipoproteins; lysosomal degradation; Mice; PCSK9; PCSK9 Inhibitors - pharmacology; Receptors, LDL - genetics; Receptors, LDL - metabolism; small-molecule; statins
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1016/j.jlr.2022.100293

Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibits the clearance of low-density lipoprotein (LDL) cholesterol (LDL-C) from plasma by directly binding with the LDL receptor (LDLR) and sending the receptor for lysosomal degradation. As the interaction promotes elevated plasma LDL-C levels, and therefore a predisposition to cardiovascular disease, PCSK9 has attracted intense interest as a therapeutic target. Despite this interest, an orally bioavailable small-molecule inhibitor of PCSK9 with extensive lipid-lowering activity is yet to enter the clinic. We report herein the discovery of NYX-PCSK9i, an orally bioavailable small-molecule inhibitor of PCSK9 with significant cholesterol-lowering activity in hyperlipidemic APOE∗3-Leiden.CETP mice. NYX-PCSK9i emerged from a medicinal chemistry campaign demonstrating potent disruption of the PCSK9-LDLR interaction in vitro and functional protection of the LDLR of human lymphocytes from PCSK9-directed degradation ex vivo. APOE∗3-Leiden.CETP mice orally treated with NYX-PCSK9i demonstrated a dose-dependent decrease in plasma total cholesterol of up to 57%, while its combination with atorvastatin additively suppressed plasma total cholesterol levels. Importantly, the majority of cholesterol lowering by NYX-PCSK9i was in non-HDL fractions. A concomitant increase in total plasma PCSK9 levels and significant increase in hepatic LDLR protein expression strongly indicated on-target function by NYX-PCSK9i. Determinations of hepatic lipid and fecal cholesterol content demonstrated depletion of liver cholesteryl esters and promotion of fecal cholesterol elimination with NYX-PCSK9i treatment. All measured in vivo biomarkers of health indicate that NYX-PCSK9i has a good safety profile. NYX-PCSK9i is a potential new therapy for hypercholesterolemia with the capacity to further enhance the lipid-lowering activities of statins.