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PCSK9 inhibitors and degraders target a secreted protein that limits cholesterol uptake by the liver. Proprotein convertase subtilisin/kexin type 9 (PCSK9) was described in 2003 as neural apoptosis-regulated convertase 1 (NARC-1), a convertase expressed in liver and brain. In the same year, mutations in its gene were linked to autosomal dominant hypercholesterolemia. Secreted PCSK9 binds low-density lipoprotein (LDL) receptors and routes them to lysosomal degradation. SBC-115076 and laroprovstat are small-molecule PCSK9 inhibitors, while PF-06446846 hydrochloride selectively stalls ribosomes during PCSK9 translation. Inclisiran is a small interfering RNA (siRNA), and PCSK9 autophagic degrader 2 removes the protein through autophagy.
