PCSK9

Summary

PCSK9 (proprotein convertase subtilisin/kexin type 9, HGNC:20001) is a protein-coding gene on chromosome 1p32.3, encoding Proprotein convertase subtilisin/kexin type 9 (Q8NBP7). Crucial player in the regulation of plasma cholesterol homeostasis.

This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an autocatalytic processing event with its prosegment in the ER and is constitutively secreted as an inactive protease into the extracellular matrix and trans-Golgi network. It is expressed in liver, intestine and kidney tissues and escorts specific receptors for lysosomal degradation. It plays a role in cholesterol and fatty acid metabolism. Mutations in this gene have been associated with autosomal dominant familial hypercholesterolemia. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 255738 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypercholesterolemia, autosomal dominant, 3 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 179
• Clinical variants (ClinVar): 1,537 total — 9 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 37
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency dosage sensitivity unlikely, triplosensitivity no evidence
• MANE Select transcript: NM_174936

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20001
Approved symbol	PCSK9
Name	proprotein convertase subtilisin/kexin type 9
Location	1p32.3
Locus type	gene with protein product
Status	Approved
Aliases	NARC-1, FH3
Ensembl gene	ENSG00000169174
Ensembl biotype	protein_coding
OMIM	607786
Entrez	255738

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 6 protein_coding, 4 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000302118, ENST00000490692, ENST00000673662, ENST00000673726, ENST00000673903, ENST00000673913, ENST00000710286, ENST00000713785, ENST00000713786, ENST00000713787, ENST00000854983, ENST00000923576

RefSeq mRNA: 9 — MANE Select: NM_174936 NM_001407240, NM_001407241, NM_001407242, NM_001407243, NM_001407244, NM_001407245, NM_001407246, NM_001407247, NM_174936

CCDS: CCDS603

Canonical transcript exons

ENST00000302118 — 12 exons

Exon	Start	End
ENSE00001279161	55046523	55046646
ENSE00001279167	55043843	55044034
ENSE00004021261	55039548	55040044
ENSE00004021262	55057331	55057514
ENSE00004021264	55063369	55064852
ENSE00004021265	55061375	55061556
ENSE00004021266	55058036	55058209
ENSE00004021268	55052278	55052411
ENSE00004021269	55055993	55056189
ENSE00004021270	55052650	55052791
ENSE00004021273	55059486	55059663
ENSE00004021274	55058499	55058647

Expression profiles

Bgee: expression breadth ubiquitous, 147 present calls, max score 91.35.

FANTOM5 (CAGE): breadth broad, TPM avg 7.1860 / max 366.4377, expressed in 649 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2976	6.3706	637
2977	0.8076	272
2978	0.0078	1

Top tissues by expression

249 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	91.35	gold quality
mucosa of transverse colon	UBERON:0004991	85.93	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.82	gold quality
cerebellar hemisphere	UBERON:0002245	85.66	gold quality
cerebellar cortex	UBERON:0002129	85.54	gold quality
buccal mucosa cell	CL:0002336	85.49	gold quality
right hemisphere of cerebellum	UBERON:0014890	85.02	gold quality
cerebellum	UBERON:0002037	84.82	gold quality
liver	UBERON:0002107	84.72	gold quality
secondary oocyte	CL:0000655	78.94	gold quality
oocyte	CL:0000023	78.49	silver quality
pancreatic ductal cell	CL:0002079	78.11	silver quality
upper lobe of left lung	UBERON:0008952	76.94	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	76.72	gold quality
right lung	UBERON:0002167	76.23	gold quality
upper lobe of lung	UBERON:0008948	76.15	gold quality
lower esophagus mucosa	UBERON:0035834	75.93	gold quality
cortical plate	UBERON:0005343	74.93	gold quality
cerebellar vermis	UBERON:0004720	74.52	silver quality
gingival epithelium	UBERON:0001949	74.51	gold quality
ileal mucosa	UBERON:0000331	74.16	gold quality
body of pancreas	UBERON:0001150	73.70	gold quality
endothelial cell	CL:0000115	72.10	gold quality
esophagus mucosa	UBERON:0002469	71.88	gold quality
gingiva	UBERON:0001828	71.74	gold quality
lung	UBERON:0002048	71.08	gold quality
tendon of biceps brachii	UBERON:0008188	70.16	gold quality
pancreas	UBERON:0001264	69.77	gold quality
ventricular zone	UBERON:0003053	69.50	gold quality
myocardium	UBERON:0002349	69.26	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7008	yes	206.25
E-ANND-3	yes	17.14

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HINFP, HNF1A, HNF4A, KAT7, NR1H4, PPARA, PPARG, SREBF1, SREBF2, TCF3

miRNA regulators (miRDB)

49 targeting PCSK9, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-1912-3P	99.32	67.40	936
HSA-MIR-7158-5P	99.25	67.95	796
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-1295B-5P	99.03	67.50	810
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-1537-5P	98.70	68.33	999

Functional genomics

ClinGen dosage: haploinsufficiency 40 (dosage sensitivity unlikely), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause autosomal dominant hypercholesterolemia (PMID:12730697)
• A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Mutation screening of genes in the region of interest identified a single nucleotide variant (G–>T). (PMID:14727179)
• mutations in the PCSK9 gene cause autosomal dominant hypercholesterolemia. (PMID:15099351)
• The effect of the S127R mutation of PCSK9 on plasma cholesterol homeostasis is mainly related to an overproduction of apolipoprotein B100. (PMID:15166014)
• PCSK9 regulation is typical of that of cholesterogenic genes, suggesting a role in cholesterol homeostasis. Human, mouse, and rat PCSK9 promoters contain 2 typical conserved motifs for cholesterol regulation: a sterol regulatory element & an Sp1 site. (PMID:15178557)
• NARC-1 has a role in regulating both the level of LDLR and that of circulating apoB-containing lipoproteins in an LDLR-dependent and -independent fashion (PMID:15358785)
• PCSK9 has a role in LDL clearance but not in apoB-containing lipoprotein production (PMID:15741654)
• The cause of unusually severe dominant hypercholesterolemia is due to the effect of mutant PCKS9 on apolipoprotein B secretion. (PMID:15772090)
• Rare missense mutations of PCSK9 may worsen the clinical phenotype of familial hypercholesterolemia patients carrying LDLR mutations. (PMID:16183066)
• Mutations in the PCSK9 gene are associated with variable phenotype of autosomal dominant hypercholesterolemia. (PMID:16211558)
• British PCSK9 patients with the D374Y mutation have an unpredictably severe clinical phenotype (PMID:16224054)
• Genetic polymorphisms are not associated with Alzheimer disease and cholesterol in Japanese patients. (PMID:16314752)
• PCSK9 proximal promoter contains a functional sterol regulatory element binding transcription factor (SREBP-1c) located from 335 bp to 355 bp upstream of the ATG. (PMID:16407292)
• A spectrum of sequence variations of PCSK9 ranging in frequency (from 0.2% to 34%) and magnitude of effect (from a 3% increase to a 49% decrease) contribute to interindividual differences in LDL-C levels. (PMID:16465619)
• nonsense mutations in PCSK9 were associated with a reduction in mean LDL cholesterol and a reduction in the risk of coronary heart disease (PMID:16554528)
• PCSK9 (or a factor acted upon by PCSK9) is secreted from transfected cells and degrades low-density lipoprotein receptors both in transfected and untransfected cells. (PMID:16571601)
• A c.43_44insCTG variation in PCSK9 plays a role in lowering cholesterol in the general population. (PMID:16619215)
• In a European population the E670G SNP in the PCSK9 gene is associated with increased LDL in men but not in women (PMID:16875509)
• PCSK9 plays a major role in determining plasma levels of LDL-C. (PMID:16909389)
• PCSK9 levels are finely regulated by the basic amino acid convertases furin and PC5/6A (PMID:16912035)
• the PCSK9 C679X variant has a marked cholesterol-lowering effect. (PMID:16989838)
• secreted PCSK9 associates with the LDL receptors and reduces hepatic LDL receptors protein levels (PMID:17080197)
• Mutations and variations occur in hypercholesterolemia–a regulator of cholesterol metabolism. (PMID:17101087)
• In a Japanese population, four missense mutations and one nonsense mutation inPCSK9 were identified only in individuals with low LDL-C; six missense mutations were identified only in individuals with high LDL-Cholesterol . (PMID:17316651)
• PCSK9-mediated degradation of the LDLR appears to take place intracellularly and occurs even when endocytosis through clathrin-coated pits is blocked by hypertonic medium. (PMID:17328821)
• REVIEW OF ROLE OF PCSK9 AND PROPROTEIN CONVERTASES IN LIPID METABOLISM, DYSLIPIDEMIAS, AND CARDIOVASCULAR DISORDERS. (PMID:17351764)
• PCSK9 is definitely a major actor in cholesterol homeostasis–review (PMID:17391637)
• PCSK9 binds the extracellular domain of LDL receptor; the D374Y gain-of-function mutant, associated with hypercholesterolemia and early-onset cardiovascular disease, binds the receptor 25 times more tightly than wild-type PCSK9 (PMID:17435765)
• secreted PCSK9 retains biological activity, is able to bind directly to the LDLR extracellular domain, and undergoes LDLR-ARH-mediated endocytosis, leading to accelerated intracellular degradation of the LDLR. (PMID:17449864)
• proprotein convertase subtilisin/kexin type 9 binding to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation (PMID:17452316)
• The sorting of PCSK9 to the cell surface and endosomes is required for PCSK9 to fully promote LDLR degradation. (PMID:17461796)
• PCSK9 promotes the degradation of the LDL receptor in hepatocytes apparently both intracellularly and by being a secreted protein that can bind the LDL receptor and be internalized [review] (PMID:17495605)
• Crystal structure is reported; its LDLR-lowering mechanism remains uncertain. The C-terminal domain has a novel protein fold and may mediate protein-protein interactions. (PMID:17502100)
• PCSK9 functions as a chaperone to prevent LDLR recycling and/or to target LDLRs for lysosomal degradation (PMID:17537735)
• study analyzed association of 1 missense (R46L) & 2 nonsense (Y142X & C679X) PCSK9 mutations with serum LDL cholesterol in African-Americans & whites; results show these variants are associated with lower LDL cholesterol levels starting in childhood (PMID:17599443)
• These results suggest a gender difference in PCSK9 regulation and function with PCSK9 correlated to total cholesterol and high density lipoprotein cholesterol in men but not women. (PMID:17645871)
• The circulating concentrations of human PCSK9 are directly correlated with LDL and total cholesterol concentrations. (PMID:17702855)
• PCSK9 mediated inhibition of the LDL receptor does not require PCSK9 autocatalytic cleavage or secretion, suggesting that PCSK9 may also function intracellularly. (PMID:17765244)
• The self-inhibited structure of full-length PCSK9 at 1.9A reveals structural homology with resistin within the C-terminal domain. (PMID:17804797)
• PCSK9 gene is a risk factor of large-vessel atherosclerosis stroke (PMID:17940607)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pcsk9	ENSDARG00000074185
mus_musculus	Pcsk9	ENSMUSG00000044254
rattus_norvegicus	Pcsk9	ENSRNOG00000006280
drosophila_melanogaster	Fur2	FBGN0004598
caenorhabditis_elegans	kpc-1	WBGENE00002232

Paralogs (9): PCSK5 (ENSG00000099139), PCSK4 (ENSG00000115257), PCSK2 (ENSG00000125851), TPP2 (ENSG00000134900), PCSK6 (ENSG00000140479), FURIN (ENSG00000140564), MBTPS1 (ENSG00000140943), PCSK7 (ENSG00000160613), PCSK1 (ENSG00000175426)

Protein

Protein identifiers

Proprotein convertase subtilisin/kexin type 9 — Q8NBP7 (reviewed: Q8NBP7)

Alternative names: Neural apoptosis-regulated convertase 1, Proprotein convertase 9, Subtilisin/kexin-like protease PC9

All UniProt accessions (8): Q8NBP7, A0A669KAY4, A0A669KB81, A0A669KBG0, A0AA34QVH0, A0AAQ5BGU8, A0AAQ5BGX4, A0AAQ5BGZ8

UniProt curated annotations — full annotation on UniProt →

Function. Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways.

Subunit / interactions. Monomer. Can self-associate to form dimers and higher multimers which may have increased LDLR degrading activity. The precursor protein but not the mature protein may form multimers. Interacts with APOB, VLDLR, LRP8/APOER2 and BACE1. The full-length immature form (pro-PCSK9) interacts with SCNN1A, SCNN1B and SCNN1G. The pro-PCSK9 form (via C-terminal domain) interacts with LDLR. Interacts (via the C-terminal domain) with ANXA2 (via repeat Annexin 1); the interaction inhibits the degradation of LDLR.

Subcellular location. Cytoplasm. Secreted. Endosome. Lysosome. Cell surface. Endoplasmic reticulum. Golgi apparatus.

Tissue specificity. Expressed in neuro-epithelioma, colon carcinoma, hepatic and pancreatic cell lines, and in Schwann cells.

Post-translational modifications. Cleavage by furin and PCSK5 generates a truncated inactive protein that is unable to induce LDLR degradation. Undergoes autocatalytic cleavage in the endoplasmic reticulum to release the propeptide from the N-terminus and the cleavage of the propeptide is strictly required for its maturation and activation. The cleaved propeptide however remains associated with the catalytic domain through non-covalent interactions, preventing potential substrates from accessing its active site. As a result, it is secreted from cells as a propeptide-containing, enzymatically inactive protein. Phosphorylation protects the propeptide against proteolysis.

Disease relevance. Hypercholesterolemia, familial, 3 (FHCL3) [MIM:603776] A form of hypercholesterolemia, a disorder of lipoprotein metabolism characterized by elevated serum low-density lipoprotein (LDL) cholesterol levels, which result in excess deposition of cholesterol in tissues and leads to xanthelasma, xanthomas, accelerated atherosclerosis and increased risk of premature coronary heart disease. FHCL3 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Its proteolytic activity is autoinhibited by the non-covalent binding of the propeptide to the catalytic domain. Inhibited by EGTA.

Domain organisation. The C-terminal domain (CRD) is essential for the LDLR-binding and degrading activities. The catalytic domain is responsible for mediating its self-association.

Polymorphism. Variant Leu-23 ins polymorphism in PCSK9 might have a modifier effect on LDLR mutation and familial hypercholesterolemia. Genetic variations in PCSK9 define the low density lipoprotein cholesterol level quantitative trait locus 1 (LDLCQ1) [MIM:603776].

Similarity. Belongs to the peptidase S8 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8NBP7-1	1	yes
Q8NBP7-2	2

RefSeq proteins (9): NP_001394169, NP_001394170, NP_001394171, NP_001394172, NP_001394173, NP_001394174, NP_001394175, NP_001394176, NP_777596* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000209	Peptidase_S8/S53_dom	Domain
IPR010259	S8pro/Inhibitor_I9	Domain
IPR015500	Peptidase_S8_subtilisin-rel	Family
IPR034193	PCSK9_ProteinaseK-like	Domain
IPR036852	Peptidase_S8/S53_dom_sf	Homologous_superfamily
IPR037045	S8pro/Inhibitor_I9_sf	Homologous_superfamily
IPR041051	PCSK9_C3	Domain
IPR041052	PCSK9_C2	Domain
IPR041254	PCSK9_C1	Domain
IPR050131	Peptidase_S8_subtilisin-like	Family

Pfam: PF00082, PF05922, PF18459, PF18463, PF18464

Enzyme classification (BRENDA):

• EC 3.4.21.61 — Kexin (BRENDA: 9 organisms, 84 substrates, 175 inhibitors, 9 Km, 8 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
AC-AYKK 4-METHYLCOUMARIN 7-AMIDE	0.35	1
AC-NLE-TYR-LYS-ARG 4-METHYLCOUMARIN 7-AMIDE	0.001	1
AC-NLE-YKK 4-METHYLCOUMARIN 7-AMIDE	0.038	1
AC-NLE-YKR 4-METHYLCOUMARIN 7-AMIDE	0.001	1
BENZYLOXYCARBONYL-ALA-TYR-LYS-LYS 4-METHYLCOUMAR	0.023	1
D-AC-NLE-TYR-LYS-ARG 4-METHYLCOUMARIN 7-AMIDE	0.001	1
T-BUTYLOXYCARBONYL-QGR 4-METHYLCOUMARIN 7-AMIDE	0.32	1
T-BUTYLOXYCARBONYL-EKK 4-METHYLCOUMARIN 7-AMIDE	—	0

UniProt features (147 total): strand 51, sequence variant 41, helix 15, disulfide bond 11, turn 7, modified residue 3, splice variant 3, active site 3, mutagenesis site 3, site 2, domain 2, signal peptide 1, propeptide 1, glycosylation site 1, chain 1, region of interest 1, sequence conflict 1

Structure

Experimental structures (PDB)

65 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7S5H	X-RAY DIFFRACTION	1.27
6XIC	X-RAY DIFFRACTION	1.38
6XIE	X-RAY DIFFRACTION	1.43
9HZ3	X-RAY DIFFRACTION	1.43
6XID	X-RAY DIFFRACTION	1.48
6U26	X-RAY DIFFRACTION	1.53
6XIB	X-RAY DIFFRACTION	1.55
9SZY	X-RAY DIFFRACTION	1.76
6XIF	X-RAY DIFFRACTION	1.77
10SB	X-RAY DIFFRACTION	1.83
4NMX	X-RAY DIFFRACTION	1.85
2QTW	X-RAY DIFFRACTION	1.9
8WFR	X-RAY DIFFRACTION	1.95
8FVL	X-RAY DIFFRACTION	1.96
8VDV	X-RAY DIFFRACTION	1.97
2P4E	X-RAY DIFFRACTION	1.98
6U2P	X-RAY DIFFRACTION	2.04
7S5G	X-RAY DIFFRACTION	2.04
6MV5	X-RAY DIFFRACTION	2.1
6U2N	X-RAY DIFFRACTION	2.15
5VLK	X-RAY DIFFRACTION	2.2
7ANQ	X-RAY DIFFRACTION	2.2
6E4Z	X-RAY DIFFRACTION	2.2
6E4Y	X-RAY DIFFRACTION	2.24
2PMW	X-RAY DIFFRACTION	2.3
2W2N	X-RAY DIFFRACTION	2.3
3H42	X-RAY DIFFRACTION	2.3
5OCA	X-RAY DIFFRACTION	2.3
2W2Q	X-RAY DIFFRACTION	2.33
5VLL	X-RAY DIFFRACTION	2.37

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NBP7-F1	85.03	0.67

Antibody-complex structures (SAbDab): 15 — 2XTJ, 3H42, 3SQO, 4K8R, 5OCA, 5VL7, 5VLP, 6E4Y, 6E4Z, 6MV5, 6U2F, 6U36, 6U38, 6U3I, 7ANQ

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (5): 218–219 (cleavage; by furin and pcsk5); 186 (charge relay system); 226 (charge relay system); 386 (charge relay system); 152–153 (cleavage; by autolysis)

Post-translational modifications (3): 38, 47, 688

Disulfide bonds (11): 223–255, 323–358, 457–527, 477–526, 486–509, 534–601, 552–600, 562–588, 608–679, 626–678, 635–654

Glycosylation sites (1): 533

Mutagenesis-validated functional residues (3):

Position	Phenotype
67	does not affect multimerization or zymogen processing.
226	remains in the endoplasmic reticulum and is not secreted.
533	1.5 kda decrease of the apparent molecular mass of pro-pcsk9 and pcsk9 and no effect on processing and secretion.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-8866427	VLDLR internalisation and degradation
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-8964038	LDL clearance

MSigDB gene sets: 315 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_LYSOSOMAL_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_SODIUM_ION_TRANSPORT, GOBP_STEROL_HOMEOSTASIS, GOBP_LIPOPROTEIN_METABOLIC_PROCESS, GOCC_VACUOLAR_MEMBRANE, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOCC_CELL_SURFACE, GOBP_NEGATIVE_REGULATION_OF_ENDOCYTOSIS

GO Biological Process (30): kidney development (GO:0001822), liver development (GO:0001889), negative regulation of receptor recycling (GO:0001920), negative regulation of receptor internalization (GO:0002091), positive regulation of receptor internalization (GO:0002092), triglyceride metabolic process (GO:0006641), phospholipid metabolic process (GO:0006644), apoptotic process (GO:0006915), lysosomal transport (GO:0007041), cholesterol metabolic process (GO:0008203), cellular response to starvation (GO:0009267), negative regulation of low-density lipoprotein particle clearance (GO:0010989), protein autoprocessing (GO:0016540), neurogenesis (GO:0022008), neuron differentiation (GO:0030182), low-density lipoprotein particle receptor catabolic process (GO:0032802), positive regulation of low-density lipoprotein particle receptor catabolic process (GO:0032805), cellular response to insulin stimulus (GO:0032869), lipoprotein metabolic process (GO:0042157), cholesterol homeostasis (GO:0042632), regulation of neuron apoptotic process (GO:0043523), positive regulation of neuron apoptotic process (GO:0043525), negative regulation of sodium ion import across plasma membrane (GO:1903783), negative regulation of receptor-mediated endocytosis involved in cholesterol transport (GO:1905601), proteolysis (GO:0006508), lipid metabolic process (GO:0006629), steroid metabolic process (GO:0008202), protein processing (GO:0016485), low-density lipoprotein receptor particle metabolic process (GO:0032799), regulation of low-density lipoprotein particle receptor catabolic process (GO:0032803)

GO Molecular Function (16): RNA binding (GO:0003723), endopeptidase activity (GO:0004175), serine-type endopeptidase activity (GO:0004252), sodium channel inhibitor activity (GO:0019871), low-density lipoprotein particle binding (GO:0030169), signaling receptor inhibitor activity (GO:0030547), apolipoprotein binding (GO:0034185), very-low-density lipoprotein particle binding (GO:0034189), apolipoprotein receptor binding (GO:0034190), low-density lipoprotein particle receptor binding (GO:0050750), very-low-density lipoprotein particle receptor binding (GO:0070326), transporter inhibitor activity (GO:0141110), protein binding (GO:0005515), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (19): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), lysosome (GO:0005764), lysosomal membrane (GO:0005765), early endosome (GO:0005769), late endosome (GO:0005770), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), cell surface (GO:0009986), COPII-coated ER to Golgi transport vesicle (GO:0030134), extrinsic component of external side of plasma membrane (GO:0031232), endolysosome membrane (GO:0036020), perinuclear region of cytoplasm (GO:0048471), PCSK9-LDLR complex (GO:1990666), PCSK9-AnxA2 complex (GO:1990667), endosome (GO:0005768)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Plasma lipoprotein clearance	2
Metabolism of proteins	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
endomembrane system	3
regulation of receptor internalization	2
receptor internalization	2
cell differentiation	2
peptidase activity	2
lipoprotein particle binding	2
molecular function inhibitor activity	2
protein binding	2
lipoprotein particle receptor binding	2
endosome	2
intracellular membrane-bounded organelle	2
protein-containing complex	2
animal organ development	1
renal system development	1
gland development	1
hepaticobiliary system development	1
receptor recycling	1
regulation of receptor recycling	1
negative regulation of macromolecule metabolic process	1
negative regulation of signaling	1
negative regulation of receptor-mediated endocytosis	1
positive regulation of receptor-mediated endocytosis	1
acylglycerol metabolic process	1
lipid metabolic process	1
organophosphate metabolic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
vacuolar transport	1
sterol metabolic process	1
secondary alcohol metabolic process	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
negative regulation of lipoprotein particle clearance	1
regulation of low-density lipoprotein particle clearance	1
low-density lipoprotein particle clearance	1
protein processing	1

Protein interactions and networks

STRING

2840 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PCSK9	APOB	P04114	986
PCSK9	HMGCR	P04035	900
PCSK9	PCSK5	Q92824	868
PCSK9	SORT1	Q99523	867
PCSK9	EGF	P01133	827
PCSK9	RHOC	P08134	823
PCSK9	LDLRAP1	Q5SW96	808
PCSK9	PSRC1	Q6PGN9	804
PCSK9	CELSR2	Q9HCU4	798
PCSK9	SCARB1	Q8WTV0	792
PCSK9	SREBF2	Q12772	785
PCSK9	CETP	P11597	782
PCSK9	ANGPTL3	Q9Y5C1	771
PCSK9	APOA1	P02647	764
PCSK9	VLDLR	P98155	749

IntAct

71 interactions, top by confidence:

A	B	Type	Score
LDLR	PCSK9	psi-mi:“MI:0407”(direct interaction)	0.680
PCSK9	LDLR	psi-mi:“MI:0407”(direct interaction)	0.680
CRIPTO	AIP	psi-mi:“MI:0914”(association)	0.640
PCSK9	MMP2	psi-mi:“MI:0194”(cleavage reaction)	0.620
PCSK9	MMP2	psi-mi:“MI:0407”(direct interaction)	0.620
ANXA2	PCSK9	psi-mi:“MI:0915”(physical association)	0.610
PCSK9	ANXA2	psi-mi:“MI:0915”(physical association)	0.610
PCSK9	ANXA2	psi-mi:“MI:0403”(colocalization)	0.610
ADAMTS4	MANBA	psi-mi:“MI:0914”(association)	0.530
C1orf54	EXTL3	psi-mi:“MI:0914”(association)	0.530
PCSK9		psi-mi:“MI:0915”(physical association)	0.520
	PCSK9	psi-mi:“MI:0915”(physical association)	0.520
FAM20C	PCSK9	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
LDLR	MMP2	psi-mi:“MI:0915”(physical association)	0.400
PCSK9	SEC11C	psi-mi:“MI:0915”(physical association)	0.400
ARMC6		psi-mi:“MI:0914”(association)	0.350
LY86	TMEM131L	psi-mi:“MI:0914”(association)	0.350

BioGRID (83): UGGT1 (Affinity Capture-MS), PDIA4 (Affinity Capture-MS), SLC25A1 (Affinity Capture-MS), DNAJA1 (Affinity Capture-MS), CLGN (Affinity Capture-MS), DNAJA2 (Affinity Capture-MS), BIRC2 (Affinity Capture-MS), TRAF2 (Affinity Capture-MS), SLC25A10 (Affinity Capture-MS), DNAJB11 (Affinity Capture-MS), CDIPT (Affinity Capture-MS), DNAJC10 (Affinity Capture-MS), DNAJA3 (Affinity Capture-MS), RHOT1 (Affinity Capture-MS), AGK (Affinity Capture-MS)

ESM2 similar proteins: A0A140LHF2, A2AJ76, A6H8M9, A8T688, D3YXG0, E7FF10, O60500, P0C0L4, P0C0L5, P21709, P35590, P43121, P50895, P55144, P55146, P59996, P85171, Q00657, Q05695, Q06805, Q06806, Q0PMG2, Q13308, Q3UH53, Q53RD9, Q60750, Q62786, Q7Z5N4, Q8BKG3, Q8HW98, Q8IZJ3, Q8N0Z9, Q8NBP7, Q8NDA2, Q8NFP4, Q8TDY8, Q923P0, Q96MS0, Q96NU0, Q96RW7

Diamond homologs: A1CIA7, A1XIH0, A1XIH1, A1XIH3, A1XIH4, A1XIH6, A7UKV6, A8T644, A8T650, A8T655, A8T658, A8T662, A8T666, A8T672, A8T677, A8T682, A8T688, A8T695, A8T6A1, A8T6A6, B0Y473, B3V0K8, B6VA84, B7ZK61, B8XGQ4, B8XGQ7, C5FH27, C5FII2, C5FJA5, C5FMY5, C5FPS1, C5FQI3, C5FXZ6, C5PCB1, C5PFR5, C5PGK9, D4AKU9, D4ALV9, D4APA9, D4AWY5

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
HNF4A	“up-regulates quantity by expression”	PCSK9	“transcriptional regulation”
SREBF2	“up-regulates quantity by expression”	PCSK9	“transcriptional regulation”
SREBF1	“up-regulates quantity by expression”	PCSK9	“transcriptional regulation”
FAM20C	“up-regulates activity”	PCSK9	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 72 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Neutrophil degranulation	12	5.4×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

1537 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	4
Uncertain significance	758
Likely benign	503
Benign	35

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
2027927	NM_174936.4(PCSK9):c.381T>G (p.Ser127Arg)	Pathogenic
2874	NM_174936.4(PCSK9):c.646T>C (p.Phe216Leu)	Pathogenic
431555	NM_174936.4(PCSK9):c.42_43insTG (p.Leu15fs)	Pathogenic
440706	NM_174936.4(PCSK9):c.140C>G (p.Ser47Cys)	Pathogenic
440712	NM_174936.4(PCSK9):c.248A>C (p.Lys83Thr)	Pathogenic
440715	NM_174936.4(PCSK9):c.323T>C (p.Leu108Pro)	Pathogenic
440721	NM_174936.4(PCSK9):c.1402A>G (p.Thr468Ala)	Pathogenic
440722	NM_174936.4(PCSK9):c.1411G>T (p.Ala471Ser)	Pathogenic
440725	NM_174936.4(PCSK9):c.2005G>C (p.Glu669Gln)	Pathogenic
1015123	NM_174936.4(PCSK9):c.653G>C (p.Arg218Thr)	Likely pathogenic
1120257	NM_174936.4(PCSK9):c.1906A>C (p.Ser636Arg)	Likely pathogenic
4277664	NM_174936.4(PCSK9):c.399+1G>A	Likely pathogenic
438337	NM_174936.4(PCSK9):c.1061A>T (p.Asn354Ile)	Likely pathogenic

SpliceAI

1961 predictions. Top by Δscore:

Variant	Effect	Δscore
1:55043833:A:AG	acceptor_gain	1.0000
1:55043833:AT:A	acceptor_gain	1.0000
1:55043833:ATG:A	acceptor_gain	1.0000
1:55043833:ATGG:A	acceptor_gain	1.0000
1:55043833:ATGGG:A	acceptor_gain	1.0000
1:55043834:T:G	acceptor_gain	1.0000
1:55044011:A:G	donor_gain	1.0000
1:55044031:GCTG:G	donor_gain	1.0000
1:55044032:CTGG:C	donor_loss	1.0000
1:55044033:TGGT:T	donor_loss	1.0000
1:55044034:GGT:G	donor_loss	1.0000
1:55044035:G:C	donor_loss	1.0000
1:55044035:G:GG	donor_gain	1.0000
1:55044036:T:A	donor_loss	1.0000
1:55046511:T:TA	acceptor_gain	1.0000
1:55046512:G:A	acceptor_gain	1.0000
1:55046521:A:AG	acceptor_gain	1.0000
1:55046522:G:GG	acceptor_gain	1.0000
1:55046645:CGGT:C	donor_loss	1.0000
1:55046646:GGT:G	donor_loss	1.0000
1:55046647:G:GG	donor_gain	1.0000
1:55046647:GTA:G	donor_loss	1.0000
1:55046648:T:G	donor_loss	1.0000
1:55052258:A:AG	acceptor_gain	1.0000
1:55052260:A:AG	acceptor_gain	1.0000
1:55052260:AAAT:A	acceptor_gain	1.0000
1:55052261:A:G	acceptor_gain	1.0000
1:55052262:A:G	acceptor_gain	1.0000
1:55052262:AT:A	acceptor_gain	1.0000
1:55052262:ATGTC:A	acceptor_gain	1.0000

AlphaMissense

4470 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:55046551:T:A	I143N	0.985
1:55057422:C:A	A363D	0.982
1:55057341:T:A	V336D	0.976
1:55056073:A:C	S294R	0.973
1:55056075:C:A	S294R	0.973
1:55056075:C:G	S294R	0.973
1:55046542:T:A	V140D	0.972
1:55058606:A:C	S488R	0.970
1:55058608:T:A	S488R	0.970
1:55058608:T:G	S488R	0.970
1:55057503:C:A	A390D	0.968
1:55046559:G:C	D146H	0.966
1:55044000:T:C	F122S	0.963
1:55057427:G:T	G365W	0.963
1:55059507:T:A	C509S	0.963
1:55059508:G:C	C509S	0.963
1:55057343:G:T	G337W	0.960
1:55057396:C:A	N354K	0.958
1:55057396:C:G	N354K	0.958
1:55043867:T:G	Y78D	0.955
1:55059507:T:C	C509R	0.955
1:55057496:G:C	A388P	0.954
1:55057497:C:A	A388D	0.954
1:55056137:C:A	A315D	0.953
1:55056094:T:C	C301R	0.950
1:55057401:G:T	G356V	0.950
1:55057466:T:C	C378R	0.947
1:55057468:C:G	C378W	0.947
1:55057469:T:C	F379L	0.947
1:55057471:T:A	F379L	0.947

dbSNP variants (sampled 300 via entrez): RS1000102689 (1:55061757 C>T), RS1000127865 (1:55051274 G>A), RS1000240386 (1:55040701 C>A,T), RS1000288995 (1:55045566 G>C,T), RS1000386173 (1:55046958 G>T), RS1000700194 (1:55063205 G>A), RS1000735676 (1:55056032 T>C), RS1000746222 (1:55040310 G>A,C), RS1000801740 (1:55057628 G>A), RS1001127561 (1:55050106 C>A,G), RS1001141931 (1:55045855 G>A), RS1001234636 (1:55053359 G>C), RS1001392299 (1:55048457 T>C), RS1001548344 (1:55064472 G>A,T), RS1001708459 (1:55053614 G>A)

Disease associations

OMIM: gene MIM:607786 | disease phenotypes: MIM:603776, MIM:143890

GenCC curated gene-disease

Disease	Classification	Inheritance
hypercholesterolemia, autosomal dominant, 3	Definitive	Autosomal dominant
homozygous familial hypercholesterolemia	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hypercholesterolemia, autosomal dominant, 3	Definitive	AD

Mondo (5): hypercholesterolemia, autosomal dominant, 3 (MONDO:0011369), familial hypercholesterolemia (MONDO:0005439), hypercholesterolemia, familial, 1 (MONDO:0007750), hypobetalipoproteinemia (MONDO:0017774), homozygous familial hypercholesterolemia (MONDO:0018328)

Orphanet (2): Homozygous familial hypercholesterolemia (Orphanet:391665), Hypobetalipoproteinemia (Orphanet:31154)

HPO phenotypes

37 total (30 of 37 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000799	Renal steatosis
HP:0000822	Hypertension
HP:0000991	Xanthomatosis
HP:0001084	Corneal arcus
HP:0001114	Xanthelasma
HP:0001138	Optic neuropathy
HP:0001397	Hepatic steatosis
HP:0001645	Sudden cardiac death
HP:0001653	Mitral regurgitation
HP:0001658	Myocardial infarction
HP:0001677	Coronary artery atherosclerosis
HP:0001681	Angina pectoris
HP:0001920	Renal artery stenosis
HP:0002094	Dyspnea
HP:0002829	Arthralgia
HP:0003077	Hyperlipidemia
HP:0003124	Hypercholesterolemia
HP:0003141	Increased LDL cholesterol concentration
HP:0004381	Supravalvular aortic stenosis
HP:0004416	Precocious atherosclerosis
HP:0004950	Peripheral arterial stenosis
HP:0004963	Calcification of the aorta
HP:0005162	Abnormal left ventricular function
HP:0005177	Premature arteriosclerosis
HP:0005181	Premature coronary artery atherosclerosis
HP:0006693	Myocardial steatosis
HP:0007201	Cerebral artery atherosclerosis
HP:0010874	Tendon xanthomatosis
HP:0012373	Abnormal eye physiology

GWAS associations

179 associations (top):

Study	Trait	p-value
GCST000132_1	LDL cholesterol	4.000000e-11
GCST000134_5	LDL cholesterol	2.000000e-44
GCST000287_8	LDL cholesterol	4.000000e-08
GCST000340_5	Myocardial infarction (early onset)	1.000000e-08
GCST000759_30	LDL cholesterol	2.000000e-28
GCST000760_23	Cholesterol, total	4.000000e-24
GCST000807_2	LDL cholesterol	1.000000e-10
GCST000998_6	Coronary heart disease	9.000000e-08
GCST001392_2	Lipid metabolism phenotypes	1.000000e-19
GCST001408_1	Response to statins (LDL cholesterol change)	5.000000e-09
GCST001639_11	Metabolite levels	5.000000e-13
GCST002042_1	LDL cholesterol	2.000000e-17
GCST002221_27	Cholesterol, total	2.000000e-39
GCST002222_7	LDL cholesterol	3.000000e-50
GCST002896_21	Cholesterol, total	6.000000e-73
GCST002898_8	LDL cholesterol	2.000000e-92
GCST003116_42	Coronary artery disease	2.000000e-08
GCST003117_5	Myocardial infarction	7.000000e-07
GCST003214_1	Cholesterol, total	2.000000e-10
GCST003216_1	LDL cholesterol	3.000000e-11
GCST004209_1	Cholesterol, total	2.000000e-17
GCST004231_16	Total cholesterol levels	4.000000e-06
GCST004233_31	LDL cholesterol levels	9.000000e-09
GCST004233_36	LDL cholesterol levels	3.000000e-42
GCST004235_25	Total cholesterol levels	1.000000e-32
GCST004235_47	Total cholesterol levels	3.000000e-08
GCST004236_2	LDL cholesterol levels	8.000000e-07
GCST004787_1	Coronary artery disease (myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, angina or chromic ischemic heart disease)	3.000000e-10
GCST005194_11	Coronary artery disease	2.000000e-25
GCST005195_70	Coronary artery disease	2.000000e-22

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004529	lipid measurement
EFO:0007804	LDL cholesterol change measurement
EFO:0004723	coronary artery calcification
EFO:0006899	PCSK9 protein measurement
EFO:0006312	mitochondrial DNA measurement
EFO:0009932	HMG CoA reductase inhibitor use measurement
EFO:0004329	alcohol drinking
EFO:0010461	argininosuccinate measurement
EFO:0006527	smoking status measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004615	apolipoprotein B measurement
EFO:0006925	lipoprotein A measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D000090542	Homozygous Familial Hypercholesterolemia	C16.320.565.398.481.500; C18.452.584.500.500.644.475.500; C18.452.584.563.481.500; C18.452.648.398.481.500
D006995	Hypobetalipoproteinemias	C16.320.565.398.500.440; C18.452.584.500.875.440; C18.452.584.563.500.440; C18.452.648.398.500.440
C566337	Hypercholesterolemia, Autosomal Dominant, 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2929 (SINGLE PROTEIN), CHEMBL4523996 (PROTEIN-PROTEIN INTERACTION), CHEMBL6195583 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 38,627 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL255863	NILOTINIB	4	38,627

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs7552841	PCSK9		0.00	0
rs11591147	PCSK9		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — S8: Subtilisin

Most potent curated ligand interactions (8 total), top 8:

Ligand	Action	Affinity	Parameter
enlicitide	Binding	11.3	pKi
lerodalcibep	Binding	10.22	pKd
bococizumab	Binding	10.0	pKd
evolocumab	Binding	9.72	pKd
alirocumab	Binding	9.42	pKd
compound 16 [PMID: 31653597]	Binding	6.97	pKi
laroprovstat	Inhibition	6.7	pKd
SBC-115,337	Inhibition	6.3	pIC50

Binding affinities (BindingDB)

44 measured of 86 human assays (86 total across all organisms); most potent 44 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
6-(6-(((1S,3S)-3-((5-(2,2,2-trifluoroethoxyl)pyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one	KD	0.8 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
6-[6-[[(1S,3S)-3-[[5-(difluoromethoxy)pyrimidin-2-yl]amino]cyclopentyl]amino]-3-pyridinyl]-5H-pyrrolo[3,4-d]pyrimidin-7-one	KD	1.1 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
6-(6-(((1S,3S)-3-((6-cyclopropyl-1,2,4-triazin-3-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one	KD	1.2 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
6-(6-(((1S,3S)-3-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one	KD	1.2 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
6-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one	KD	1.2 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one	KD	1.4 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
6-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one	KD	1.5 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
6-(6-(((1S,3S)-3-((5-cyclopropylpyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one	KD	1.8 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
6-(6-(((1S,3S)-3-((5-(trifluoromethoxy)pyrimidin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one and 6-(6-(((1S,3S)-3-((5-(bromodifluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one	KD	2.2 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
6’-(((1S,3S)-3-(pyrrolo[2,1-f][1,2,4]triazin-2-ylamino)cyclopentyl)amino)-2H-[1,3’-bipyridinyl]-2-one	KD	2.4 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
5,5-dimethyl-6-[6-[[(1S,3S)-3-[[6-(trifluoromethyl)-1,2,4-triazin-3-yl]amino]cyclopentyl]amino]-3-pyridinyl]pyrrolo[3,4-b]pyridin-7-one	KD	2.5 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
6’-((3-(((1S,3S)-7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3’-bipyridinyl]-2-one	KD	2.6 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-7-(trifluoromethyl) isoindol-1-one	KD	2.6 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
6’-(((1S,3S)-3-((7-chloro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3’-bipyridinyl]-2-one	KD	2.7 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
6-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2-(trifluoromethyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one	KD	2.8 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
US20250326722, Example 93	KD	2.9 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
2-(6-(((1S,3S)-3-((7-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentylamino)pyridin-3-yl)-4-(trifluoromethyl) isoindol-1-one	KD	3 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
2-(6-(((1S,3S)-3-((5-(difluoromethoxy)pyrimidin-2-yl)amino)cyclopentyl)amino)-3-yl)-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one	KD	3.1 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
US20250326722, Example 145	KD	3.2 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
6’-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3’-bipyridinyl]-2-one	KD	4.2 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
6-Methyl-2-(6-(((1S,3S)-3-((7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one	KD	4.8 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
6’-(((1S,3S)-3-((7-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)cyclopentyl)amino)-2H-[1,3’-bipyridinyl]-2-one	KD	4.9 nM	US-20250326722: NITROGEN-CONTAINING HETEROCYCLIC DERIVATIVE INHIBITOR, PREPARATION METHOD THEREFOR AND USE THEREOF
N-(3-chloro-2-pyridinyl)-4-(6-methyltriazolo[4,5-b]pyridin-3-yl)-N-[(3R)-piperidin-3-yl]benzamide	IC50	800 nM	US-9227956: Substituted amide compounds
N-(3-chloro-2-pyridinyl)-N-[(3R)-piperidin-3-yl]-4-(triazolo[4,5-b]pyridin-3-yl)benzamide	IC50	800 nM	US-9227956: Substituted amide compounds
2-methyl-N-(5-methylsulfanylpyrimidin-2-yl)-N’-[6-(1H-pyrazol-4-yl)-1,3-benzothiazol-2-yl]propane-1,3-diamine	KD	1100 nM	US-11248001: PCSK9 inhibitors and methods of use thereof
2-methyl-N-(5-methylsulfanylpyrimidin-2-yl)-N’-[5-[5-(trifluoromethyl)-1H-pyrazol-4-yl]pyrazin-2-yl]propane-1,3-diamine	KD	1100 nM	US-11248001: PCSK9 inhibitors and methods of use thereof
N-(3-chloro-2-pyridinyl)-N-[(3R)-piperidin-3-yl]-5-(triazolo[4,5-b]pyridin-3-yl)pyridine-2-carboxamide	IC50	1500 nM	US-9227956: Substituted amide compounds
ethyl 4-[4-[(3-chloro-2-pyridinyl)-[(3R)-piperidin-3-yl]carbamoyl]phenyl]-1-methylpyrazole-5-carboxylate	IC50	1500 nM	US-9227956: Substituted amide compounds
methyl 4-[4-[(3-chloro-2-pyridinyl)-[(3R)-piperidin-3-yl]carbamoyl]phenyl]-1-methylpyrazole-5-carboxylate	IC50	1500 nM	US-9227956: Substituted amide compounds
N-(3-chloro-2-pyridinyl)-N-[(3R)-piperidin-3-yl]-4-pyrazolo[1,5-a]pyrimidin-3-ylbenzamide	IC50	1700 nM	US-9227956: Substituted amide compounds
N-(3-chloro-2-pyridinyl)-5-(6-methyltriazolo[4,5-b]pyridin-3-yl)-N-[(3R)-piperidin-3-yl]pyridine-2-carboxamide	IC50	1800 nM	US-9227956: Substituted amide compounds
methyl 1-methyl-4-[4-[(3-methyl-2-pyridinyl)-[(3R)-piperidin-3-yl]carbamoyl]phenyl]pyrazole-5-carboxylate	IC50	2300 nM	US-9227956: Substituted amide compounds
N-(3-methyl-2-pyridinyl)-N-[(3R)-piperidin-3-yl]-4-pyrazolo[1,5-a]pyrimidin-3-ylbenzamide	IC50	3200 nM	US-9227956: Substituted amide compounds
(5S)-3-[2-[4-(azepane-1-carbonyl)piperidin-1-yl]-2-oxoethyl]-5-methyl-5-naphthalen-2-ylimidazolidine-2,4-dione	KD	3880 nM	US-12419888: Methods of treating elevated plasma cholesterol
1-ethoxycarbonyloxyethyl 1-methyl-4-[4-[(1-methylpyrrolo[2,3-c]pyridin-7-yl)-[(3R)-piperidin-3-yl]carbamoyl]phenyl]pyrazole-5-carboxylate	IC50	4500 nM	US-9227956: Substituted amide compounds
(5S)-5-methyl-5-naphthalen-2-yl-3-[2-oxo-2-[4-(2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]imidazolidine-2,4-dione	KD	5800 nM	US-12419888: Methods of treating elevated plasma cholesterol
[(1S)-1-ethoxycarbonyloxyethyl] 4-[4-[(3-chloro-2-pyridinyl)-[(3R)-piperidin-3-yl]carbamoyl]phenyl]-1-methylpyrazole-5-carboxylate	IC50	7300 nM	US-9227956: Substituted amide compounds
1-ethoxycarbonyloxyethyl 4-[4-[(3-chloro-2-pyridinyl)-[(3R)-piperidin-3-yl]carbamoyl]phenyl]-1-methylpyrazole-5-carboxylate	IC50	9500 nM	US-9227956: Substituted amide compounds
[(1R)-1-ethoxycarbonyloxyethyl] 4-[4-[(3-chloro-2-pyridinyl)-[(3R)-piperidin-3-yl]carbamoyl]phenyl]-1-methylpyrazole-5-carboxylate	IC50	10700 nM	US-9227956: Substituted amide compounds
(1-pyridin-2-yl-1,3,4,9-tetrahydropyrido[3,4-b]indol-2-yl)-(2-thiophen-2-yl-1,3-thiazol-4-yl)methanone	KD	11000 nM	US-12419888: Methods of treating elevated plasma cholesterol
1-ethoxycarbonyloxyethyl 4-[4-[isoquinolin-1-yl-[(3R)-piperidin-3-yl]carbamoyl]phenyl]-1-methylpyrazole-5-carboxylate	IC50	11700 nM	US-9227956: Substituted amide compounds
1-[5-[1-methyl-4-[4-[(3-methyl-2-pyridinyl)-[(3R)-piperidin-3-yl]carbamoyl]phenyl]pyrazol-5-yl]tetrazol-2-yl]ethyl propan-2-yl carbonate	IC50	11800 nM	US-9227956: Substituted amide compounds
(2,6-dimethylquinolin-4-yl)-[(3S)-3-([1,2,4]triazolo[4,3-a]pyridin-3-yl)piperidin-1-yl]methanone	KD	12000 nM	US-12419888: Methods of treating elevated plasma cholesterol
1-[2-(4-methyl-4-naphthalen-2-yl-2,5-dioxoimidazolidin-1-yl)acetyl]-N-phenylpiperidine-4-carboxamide	KD	13800 nM	US-12419888: Methods of treating elevated plasma cholesterol

ChEMBL bioactivities

920 potent at pChembl≥5 of 1143 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.94	Ki	0.01136	nM	CHEMBL5084416
10.43	Ki	0.037	nM	CHEMBL5082483
9.82	IC50	0.152	nM	CHEMBL4642977
9.82	EC50	0.15	nM	CHEMBL4780905
9.80	Ki	0.16	nM	CHEMBL5081587
9.70	Ki	0.2	nM	CHEMBL5081587
9.64	Ki	0.23	nM	CHEMBL5087487
9.60	Ki	0.25	nM	CHEMBL5086286
9.55	EC50	0.28	nM	CHEMBL4785006
9.52	Kd	0.3	nM	CHEMBL5271747
9.48	IC50	0.327	nM	CHEMBL4635142
9.41	Ki	0.39	nM	CHEMBL5091040
9.37	Ki	0.43	nM	CHEMBL5086286
9.36	IC50	0.438	nM	CHEMBL4642595
9.35	Ki	0.45	nM	CHEMBL5087487
9.32	Ki	0.48	nM	CHEMBL5091040
9.24	IC50	0.57	nM	CHEMBL4641251
9.16	EC50	0.69	nM	CHEMBL4797870
9.07	IC50	0.85	nM	CHEMBL4645450
9.03	IC50	0.93	nM	CHEMBL4638184
8.94	Ki	1.16	nM	CHEMBL5094648
8.92	EC50	1.21	nM	CHEMBL4783308
8.87	Ki	1.36	nM	CHEMBL4790764
8.82	Ki	1.5	nM	CHEMBL4761415
8.82	Ki	1.5	nM	CHEMBL4782157
8.70	IC50	2	nM	CHEMBL5278292
8.68	Ki	2.1	nM	CHEMBL4759174
8.66	Ki	2.17	nM	CHEMBL5084586
8.65	Ki	2.25	nM	CHEMBL5094648
8.61	EC50	2.46	nM	CHEMBL4789986
8.57	Ki	2.7	nM	CHEMBL4789838
8.55	Ki	2.8	nM	CHEMBL4798026
8.51	IC50	3.1	nM	CHEMBL5268810
8.41	Ki	3.9	nM	CHEMBL4742833
8.40	Ki	4	nM	CHEMBL4789480
8.40	Ki	4	nM	CHEMBL4745053
8.38	Ki	4.2	nM	CHEMBL4754486
8.38	Ki	4.2	nM	CHEMBL4789893
8.38	Ki	4.2	nM	CHEMBL4755930
8.37	Ki	4.3	nM	CHEMBL4743963
8.36	Ki	4.36	nM	CHEMBL5078356
8.33	Ki	4.66	nM	CHEMBL5081995
8.32	Ki	4.83	nM	CHEMBL5081260
8.26	Kd	5.5	nM	CHEMBL5280306
8.22	Kd	6	nM	CHEMBL5088319
8.21	Kd	6.1	nM	CHEMBL5278292
8.20	Ki	6.3	nM	CHEMBL4776000
8.15	Kd	7	nM	CHEMBL5092723
8.15	IC50	7	nM	CHEMBL5418494
8.09	Ki	8.2	nM	CHEMBL4752664

PubChem BioAssay actives

267 with measured affinity, of 699 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(1S,9Z,13S,17S,20S,23S,29S,55S,60R,63S)-63-(aminomethyl)-50-fluoro-20-[(1R)-1-hydroxyethyl]-23-[(4-methoxyphenyl)methyl]-29,60-dimethyl-12-oxa-34,68-dithia-16,19,22,25,31,41,42,43,46,56,58,61,64-tridecazadecacyclo[36.19.12.13,7.116,55.136,40.141,44.146,53.013,17.025,29.047,52]tetraheptaconta-3,5,7(74),9,36(73),37,39,42,44(72),47(52),48,50,53(71)-tridecaene-18,21,24,30,57,59,62,65,70-nonone	1813380: Inhibition of human PCSK9 using Alexa Fluor 674 as substrate incubated for 2 hrs by FRET plus assay	ki	<0.0001	uM
2-[2-[3-[[(1S,9E,13S,17S,20S,23S,29S,55S,60R,63S)-50-fluoro-20-[(1R)-1-hydroxyethyl]-23-[(4-methoxyphenyl)methyl]-29,63-dimethyl-18,21,24,30,57,59,62,65,70-nonaoxo-12-oxa-34,68-dithia-16,19,22,25,31,41,42,43,46,56,58,61,64-tridecazadecacyclo[36.19.12.13,7.116,55.136,40.141,44.146,53.013,17.025,29.047,52]tetraheptaconta-3,5,7(74),9,36(73),37,39,42,44(72),47(52),48,50,53(71)-tridecaen-60-yl]methylamino]-3-oxopropoxy]ethoxy]ethyl-trimethylazanium	1813380: Inhibition of human PCSK9 using Alexa Fluor 674 as substrate incubated for 2 hrs by FRET plus assay	ki	<0.0001	uM
(1S,9E,13S,17S,20S,23S,29S,55S,60R,63S)-63-(aminomethyl)-50-fluoro-20-[(1R)-1-hydroxyethyl]-23-[(4-methoxyphenyl)methyl]-29,60-dimethyl-12-oxa-34,68-dithia-16,19,22,25,31,41,42,43,46,56,58,61,64-tridecazadecacyclo[36.19.12.13,7.116,55.136,40.141,44.146,53.013,17.025,29.047,52]tetraheptaconta-3,5,7(74),9,36(73),37,39,42,44(72),47(52),48,50,53(71)-tridecaene-18,21,24,30,57,59,62,65,70-nonone	1813380: Inhibition of human PCSK9 using Alexa Fluor 674 as substrate incubated for 2 hrs by FRET plus assay	ki	<0.0001	uM
5-[(3aR,4S,6aS)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-N-[2-[2-[3-[[(1S,9E,13S,17S,20S,23S,29S,55S,60S,63S)-50-fluoro-20-[(1S)-1-hydroxyethyl]-23-[(4-methoxyphenyl)methyl]-29,63-dimethyl-18,21,24,30,57,59,62,65,70-nonaoxo-12-oxa-34,68-dithia-16,19,22,25,31,41,42,43,46,56,58,61,64-tridecazadecacyclo[36.19.12.13,7.116,55.136,40.141,44.146,53.013,17.025,29.047,52]tetraheptaconta-3,5,7(74),9,36(73),37,39,42,44(72),47(52),48,50,53(71)-tridecaen-60-yl]methylamino]-3-oxopropoxy]ethoxy]ethyl]pentanamide	1813380: Inhibition of human PCSK9 using Alexa Fluor 674 as substrate incubated for 2 hrs by FRET plus assay	ki	<0.0001	uM
2-[2-[3-[[(1S,9E,13S,17S,20S,23S,29S,55S,60R,63S)-50-fluoro-20-[(1R)-1-hydroxyethyl]-23-[(4-methoxyphenyl)methyl]-29,60-dimethyl-18,21,24,30,57,59,62,65,70-nonaoxo-12-oxa-34,68-dithia-16,19,22,25,31,41,42,43,46,56,58,61,64-tridecazadecacyclo[36.19.12.13,7.116,55.136,40.141,44.146,53.013,17.025,29.047,52]tetraheptaconta-3,5,7(74),9,36(73),37,39,42,44(72),47(52),48,50,53(71)-tridecaen-63-yl]methylamino]-3-oxopropoxy]ethoxy]ethyl-trimethylazanium	1813380: Inhibition of human PCSK9 using Alexa Fluor 674 as substrate incubated for 2 hrs by FRET plus assay	ki	<0.0001	uM
3-[2-(2-aminoethoxy)ethoxy]-N-[[(1S,9E,13S,17S,20S,23S,29S,55S,60R,63S)-50-fluoro-20-[(1R)-1-hydroxyethyl]-23-[(4-methoxyphenyl)methyl]-29,60-dimethyl-18,21,24,30,57,59,62,65,70-nonaoxo-12-oxa-34,68-dithia-16,19,22,25,31,41,42,43,46,56,58,61,64-tridecazadecacyclo[36.19.12.13,7.116,55.136,40.141,44.146,53.013,17.025,29.047,52]tetraheptaconta-3,5,7(74),9,36(73),37,39,42,44(72),47(52),48,50,53(71)-tridecaen-63-yl]methyl]propanamide	1813381: Inhibition of human PCSK9 using Alexa Fluor 674 as substrate incubated for 2 hrs by FRET ultra assay	ki	<0.0001	uM
(7-fluoro-1H-indol-3-yl)-(6-fluoro-1-methylbenzimidazol-2-yl)methanone	1742777: Modulation of PCSK9 in human HepG2 cells assessed as reduction in PCSK9 expression incubated for 24 hrs prior to compound washout followed by compound addition and measured after 24 hrs by ELISA	ec50	0.0001	uM
(3S,7S,10S,13R)-6-[[4-chloro-2-[[6-[2-[(dimethylamino)methyl]-3-methylimidazol-4-yl]-3-pyridinyl]oxy]phenyl]methyl]-13-[(4-chlorophenyl)methyl]-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetrazabicyclo[11.3.1]heptadecane-2,5,8,11-tetrone	1662034: Inhibition of human PCSK9 by Alexa Fluor 647 staining based TR-FRET assay	ic50	0.0002	uM
(2S,5S,8S,14S,32S,35R,38S,46E,50S,54S)-35-(aminomethyl)-54-[(5-fluoro-1H-indol-3-yl)methyl]-5-[(1R)-1-methoxyethyl]-8-[(4-methoxyphenyl)methyl]-14,32-dimethyl-49-oxa-19,27-dithia-1,4,7,10,16,31,34,37,55-nonazahexacyclo[36.14.4.121,25.140,44.02,50.010,14]octapentaconta-21,23,25(58),40,42,44(57),46-heptaene-3,6,9,15,30,33,36,53,56-nonone	1813379: Inhibition of human PCSK9 using Alexa Fluor 674 as substrate incubated for 2 hrs by FRET assay	ki	0.0002	uM
(2S,5S,8S,14S,32S,35S,38S,46E,50S,54S)-32-(aminomethyl)-54-[(5-fluoro-1H-indol-3-yl)methyl]-5-[(1S)-1-methoxyethyl]-8-[(4-methoxyphenyl)methyl]-14,35-dimethyl-49-oxa-19,27-dithia-1,4,7,10,16,31,34,37,55-nonazahexacyclo[36.14.4.121,25.140,44.02,50.010,14]octapentaconta-21,23,25(58),40,42,44(57),46-heptaene-3,6,9,15,30,33,36,53,56-nonone	1813380: Inhibition of human PCSK9 using Alexa Fluor 674 as substrate incubated for 2 hrs by FRET plus assay	ki	0.0002	uM
(3R,7S,10S,13R)-3-benzyl-6-[[5-chloro-3-[4-[2-[(dimethylamino)methyl]-3-methylimidazol-4-yl]phenoxy]-2-pyridinyl]methyl]-13-[(4-chlorophenyl)methyl]-10-(methoxymethyl)-7-methyl-1,6,9,12-tetrazabicyclo[11.3.1]heptadecane-2,5,8,11-tetrone	1662034: Inhibition of human PCSK9 by Alexa Fluor 647 staining based TR-FRET assay	ic50	0.0003	uM
(1-butyl-7-fluoroindol-3-yl)-(6-fluoro-1-methylbenzimidazol-2-yl)methanone	1742777: Modulation of PCSK9 in human HepG2 cells assessed as reduction in PCSK9 expression incubated for 24 hrs prior to compound washout followed by compound addition and measured after 24 hrs by ELISA	ec50	0.0003	uM
(2S,5S,8S,14S,32S,35R,38S,46E,50S,54S)-54-[(5-fluoro-1H-indol-3-yl)methyl]-5-[(1R)-1-hydroxyethyl]-8-[(4-methoxyphenyl)methyl]-14,32,35-trimethyl-49-oxa-19,27-dithia-1,4,7,10,16,31,34,37,55-nonazahexacyclo[36.14.4.121,25.140,44.02,50.010,14]octapentaconta-21,23,25(58),40,42,44(57),46-heptaene-3,6,9,15,30,33,36,53,56-nonone	1813380: Inhibition of human PCSK9 using Alexa Fluor 674 as substrate incubated for 2 hrs by FRET plus assay	ki	0.0003	uM
2-[(3S,6S,9S,12S,15S,18S,21S,24S,27S,30S,33S,39R,42S)-39-[(2-amino-2-oxoethyl)carbamoyl]-33-benzyl-3-(3-carbamimidamidopropyl)-21,24-bis[(1R)-1-hydroxyethyl]-27-(hydroxymethyl)-9,10,15,16-tetramethyl-2,5,8,11,14,17,20,23,26,29,32,35,41-tridecaoxo-12,18-bis[(4-phenylphenyl)methyl]-30-propan-2-yl-37-thia-1,4,7,10,13,16,19,22,25,28,31,34,40-tridecazabicyclo[40.3.0]pentatetracontan-6-yl]acetic acid	1933138: Binding affinity to human PCSK9	kd	0.0003	uM
(3R,7S,10S,13R)-3-benzyl-6-[[4-chloro-2-[4-[2-[(dimethylamino)methyl]-3-methylimidazol-4-yl]phenoxy]-3-fluorophenyl]methyl]-13-[(4-chlorophenyl)methyl]-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetrazabicyclo[11.3.1]heptadecane-2,5,8,11-tetrone	1662034: Inhibition of human PCSK9 by Alexa Fluor 647 staining based TR-FRET assay	ic50	0.0004	uM
(2S,5S,8S,14S,32S,35R,38S,46E,50S,54S)-54-[(5-fluoro-1H-indol-3-yl)methyl]-5-[(1R)-1-methoxyethyl]-8-[(4-methoxyphenyl)methyl]-14,32,35-trimethyl-49-oxa-19,27-dithia-1,4,7,10,16,31,34,37,55-nonazahexacyclo[36.14.4.121,25.140,44.02,50.010,14]octapentaconta-21,23,25(58),40,42,44(57),46-heptaene-3,6,9,15,30,33,36,53,56-nonone	1813380: Inhibition of human PCSK9 using Alexa Fluor 674 as substrate incubated for 2 hrs by FRET plus assay	ki	0.0004	uM
(3S,7S,10S,13R)-6-[[4-chloro-2-fluoro-6-[4-[3-methyl-2-(methylaminomethyl)imidazol-4-yl]phenoxy]phenyl]methyl]-13-[(4-chlorophenyl)methyl]-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetrazabicyclo[11.3.1]heptadecane-2,5,8,11-tetrone	1662034: Inhibition of human PCSK9 by Alexa Fluor 647 staining based TR-FRET assay	ic50	0.0006	uM
(6-fluoro-1-methylbenzimidazol-2-yl)-[7-fluoro-1-(2-morpholin-4-ylethylsulfonyl)indol-3-yl]methanone	1742777: Modulation of PCSK9 in human HepG2 cells assessed as reduction in PCSK9 expression incubated for 24 hrs prior to compound washout followed by compound addition and measured after 24 hrs by ELISA	ec50	0.0007	uM
(3R,7S,10S,13R)-3-benzyl-6-[[4-chloro-2-[4-[3-methyl-2-(methylaminomethyl)imidazol-4-yl]phenoxy]phenyl]methyl]-13-[(4-chlorophenyl)methyl]-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetrazabicyclo[11.3.1]heptadecane-2,5,8,11-tetrone	1662034: Inhibition of human PCSK9 by Alexa Fluor 647 staining based TR-FRET assay	ic50	0.0008	uM
(3R,7S,10S,13R)-6-[[4-chloro-2-[4-[2-[(cyclobutylamino)methyl]-3-methylimidazol-4-yl]phenoxy]-6-fluorophenyl]methyl]-13-[(4-chlorophenyl)methyl]-3-(cyclopropylmethyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetrazabicyclo[11.3.1]heptadecane-2,5,8,11-tetrone	1662034: Inhibition of human PCSK9 by Alexa Fluor 647 staining based TR-FRET assay	ic50	0.0009	uM
(6-fluoro-1-methylbenzimidazol-2-yl)-(7-fluoro-1-methylindol-3-yl)methanone	1742777: Modulation of PCSK9 in human HepG2 cells assessed as reduction in PCSK9 expression incubated for 24 hrs prior to compound washout followed by compound addition and measured after 24 hrs by ELISA	ec50	0.0012	uM
(2S,5S,8S,14S,32S,35R,38S,46Z,50S,54S)-35-(aminomethyl)-54-[(5-fluoro-1H-indol-3-yl)methyl]-5-[(1R)-1-methoxyethyl]-8-[(4-methoxyphenyl)methyl]-14,32-dimethyl-49-oxa-19,27-dithia-1,4,7,10,16,31,34,37,55-nonazahexacyclo[36.14.4.121,25.140,44.02,50.010,14]octapentaconta-21,23,25(58),40,42,44(57),46-heptaene-3,6,9,15,30,33,36,53,56-nonone	1813379: Inhibition of human PCSK9 using Alexa Fluor 674 as substrate incubated for 2 hrs by FRET assay	ki	0.0012	uM
(1S,7S,10S,13S,19S,37S,40R,43S)-50-fluoro-43-[(5-fluoro-1H-indol-3-yl)methyl]-10-[(1R)-1-hydroxyethyl]-13-[(4-methoxyphenyl)methyl]-19,37,40-trimethyl-24,32-dithia-3,9,12,15,21,36,39,42,45,54,57,58,59-tridecazaoctacyclo[26.17.14.126,30.147,54.156,59.03,7.015,19.048,53]dohexaconta-26,28,30(62),47(61),48(53),49,51,56(60),57-nonaene-2,8,11,14,20,35,38,41,44-nonone	1700401: Inhibition of AlexaFluor647-tagged cyclic peptide binding to avi-tagged-biotinylated human PCSK9 measured after 2 hrs by Lance Streptavidin Europium based FRET assay	ki	0.0014	uM
(1S,4S,7S,13S,31S,34R,37S,51S)-51-[(5-fluoro-1H-indol-3-yl)methyl]-4-[(1R)-1-hydroxyethyl]-7-[(4-methoxyphenyl)methyl]-13,31,34-trimethyl-18,26-dithia-3,6,9,15,30,33,36,45,49,52-decazapentacyclo[35.11.5.120,24.139,43.09,13]pentapentaconta-20,22,24(55),39(54),40,42-hexaene-2,5,8,14,29,32,35,46,50,53-decone	1700401: Inhibition of AlexaFluor647-tagged cyclic peptide binding to avi-tagged-biotinylated human PCSK9 measured after 2 hrs by Lance Streptavidin Europium based FRET assay	ki	0.0015	uM
2-[(8S,14S,17S,20S,23S,26S,29R,32S)-32-(4-aminobutyl)-41-fluoro-23,26-bis[(5-fluoro-1H-indol-3-yl)methyl]-14-[(4-hydroxyphenyl)methyl]-17-(1H-imidazol-5-ylmethyl)-8,29-dimethyl-7,13,16,19,22,25,28,31,34-nonaoxo-3,37-dithia-6,12,15,18,21,24,27,30,33-nonazatricyclo[37.3.1.08,12]tritetraconta-1(42),39(43),40-trien-20-yl]acetic acid	1700401: Inhibition of AlexaFluor647-tagged cyclic peptide binding to avi-tagged-biotinylated human PCSK9 measured after 2 hrs by Lance Streptavidin Europium based FRET assay	ki	0.0015	uM
3-[(3S,6S,12R,15S,21S,24S,27S,30S,33S,36S,39S,42S,45S)-6-benzyl-12-(ethylcarbamoyl)-39,42-bis[(1R)-1-hydroxyethyl]-21,27,28,33,34-pentamethyl-2,5,8,14,20,23,26,29,32,35,38,41,44-tridecaoxo-30,36-bis[(4-phenylphenyl)methyl]-3-propan-2-yl-10-thia-1,4,7,13,19,22,25,28,31,34,37,40,43-tridecazatricyclo[43.3.0.015,19]octatetracontan-24-yl]propanoic acid	1933148: Inhibition of PCSK9-LDLR (unknown origin) protein-protein interaction	ic50	0.0020	uM
(5R,8S,14S,17S,20S,22S,26S,29S,32R,35S)-35-(4-aminobutyl)-22-fluoro-26,29-bis[(5-fluoro-1H-indol-3-yl)methyl]-17-[(1R)-1-hydroxyethyl]-14-[(4-hydroxyphenyl)methyl]-8,32-dimethyl-7,13,16,19,25,28,31,34,37-nonaoxo-3,40-dithia-6,12,15,18,24,27,30,33,36-nonazatetracyclo[40.3.1.08,12.020,24]hexatetraconta-1(45),42(46),43-triene-5-carboxamide	1700401: Inhibition of AlexaFluor647-tagged cyclic peptide binding to avi-tagged-biotinylated human PCSK9 measured after 2 hrs by Lance Streptavidin Europium based FRET assay	ki	0.0021	uM
(2S,5S,8S,14S,32S,35R,38S,50S,54S)-54-[(5-fluoro-1H-indol-3-yl)methyl]-5-[(1R)-1-methoxyethyl]-8-[(4-methoxyphenyl)methyl]-14,32,35-trimethyl-49-oxa-19,27-dithia-1,4,7,10,16,31,34,37,55-nonazahexacyclo[36.14.4.121,25.140,44.02,50.010,14]octapentaconta-21,23,25(58),40,42,44(57)-hexaene-3,6,9,15,30,33,36,53,56-nonone	1813379: Inhibition of human PCSK9 using Alexa Fluor 674 as substrate incubated for 2 hrs by FRET assay	ki	0.0022	uM
(6-fluoro-1H-benzimidazol-2-yl)-(7-fluoro-1H-indol-3-yl)methanone	1742777: Modulation of PCSK9 in human HepG2 cells assessed as reduction in PCSK9 expression incubated for 24 hrs prior to compound washout followed by compound addition and measured after 24 hrs by ELISA	ec50	0.0025	uM
2-[(8S,14S,17S,20S,23S,26S,29R,32S)-32-(4-aminobutyl)-23,26-bis[(5-fluoro-1H-indol-3-yl)methyl]-14-[(4-hydroxyphenyl)methyl]-17-(1H-imidazol-5-ylmethyl)-8-methyl-7,13,16,19,22,25,28,31,34-nonaoxo-29-propyl-3,37-dithia-6,12,15,18,21,24,27,30,33-nonazatricyclo[37.3.1.08,12]tritetraconta-1(42),39(43),40-trien-20-yl]acetic acid	1700401: Inhibition of AlexaFluor647-tagged cyclic peptide binding to avi-tagged-biotinylated human PCSK9 measured after 2 hrs by Lance Streptavidin Europium based FRET assay	ki	0.0027	uM
(1S,4S,7S,13S,31S,34R,37S)-51-[(6-fluoroquinolin-4-yl)methyl]-4-[(1R)-1-methoxyethyl]-7-[(4-methoxyphenyl)methyl]-13,31,34,49-tetramethyl-18,26-dithia-3,6,9,15,30,33,36,45,49,52-decazapentacyclo[35.11.5.120,24.139,43.09,13]pentapentaconta-20,22,24(55),39(54),40,42-hexaene-2,5,8,14,29,32,35,46,50,53-decone	1700401: Inhibition of AlexaFluor647-tagged cyclic peptide binding to avi-tagged-biotinylated human PCSK9 measured after 2 hrs by Lance Streptavidin Europium based FRET assay	ki	0.0028	uM
(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-1-[(2R)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S,3S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2R)-2-[[2-[[2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S,3R)-2-[(2-aminoacetyl)amino]-3-hydroxybutanoyl]amino]-4-oxobutanoyl]amino]-4-carboxybutanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-4-oxobutanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]acetyl]amino]-3-sulfanylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-methylpentanoyl]amino]-3-methylbutanoyl]amino]-3-sulfanylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]amino]-3-methylpentanoyl]amino]acetyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-carboxybutanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]pyrrolidine-2-carbonyl]amino]-3-carboxypropanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]-3-methylbutanoyl]amino]propanoyl]amino]-5-oxopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-sulfanylpropanoyl]amino]pentanedioic acid	1933140: Inhibition of human PCSK9-LDLR protein-protein interaction using EGF peptide as substrate preincubated for 30 mins followed by LDLR addition and measured after 2 hrs by ELISA	ic50	0.0031	uM
2-[(8S,14S,17S,20S,23S,26S,29R,32S)-32-(4-aminobutyl)-23,26-bis[(5-fluoro-1H-indol-3-yl)methyl]-17-(1H-imidazol-5-ylmethyl)-14-[(4-methoxyphenyl)methyl]-8,29-dimethyl-7,13,16,19,22,25,28,31,34-nonaoxo-3,37-dithia-6,12,15,18,21,24,27,30,33-nonazatricyclo[37.3.1.08,12]tritetraconta-1(42),39(43),40-trien-20-yl]acetic acid	1700401: Inhibition of AlexaFluor647-tagged cyclic peptide binding to avi-tagged-biotinylated human PCSK9 measured after 2 hrs by Lance Streptavidin Europium based FRET assay	ki	0.0039	uM
2-[(5R,8S,14S,17S,20S,23S,26S,32S)-32-(4-aminobutyl)-5-carbamoyl-23,26-bis[(5-fluoro-1H-indol-3-yl)methyl]-14-[(4-hydroxyphenyl)methyl]-17-(1H-imidazol-5-ylmethyl)-8-methyl-7,13,16,19,22,25,28,31,34-nonaoxo-3,37-dithia-6,12,15,18,21,24,27,30,33-nonazatricyclo[37.3.1.08,12]tritetraconta-1(42),39(43),40-trien-20-yl]acetic acid	1700401: Inhibition of AlexaFluor647-tagged cyclic peptide binding to avi-tagged-biotinylated human PCSK9 measured after 2 hrs by Lance Streptavidin Europium based FRET assay	ki	0.0040	uM
(1S,4S,7S,13S,31S,34R,37S,53S)-53-[(5-fluoro-1H-indol-3-yl)methyl]-4-[(1R)-1-hydroxyethyl]-7-[(4-methoxyphenyl)methyl]-13,31,34-trimethyl-18,26-dithia-3,6,9,15,30,33,36,45,51,54-decazapentacyclo[35.13.5.120,24.139,43.09,13]heptapentaconta-20,22,24(57),39(56),40,42-hexaene-2,5,8,14,29,32,35,46,52,55-decone	1700401: Inhibition of AlexaFluor647-tagged cyclic peptide binding to avi-tagged-biotinylated human PCSK9 measured after 2 hrs by Lance Streptavidin Europium based FRET assay	ki	0.0040	uM
2-[(8S,14S,17S,20S,23S,26S,29R,32S)-32-(4-aminobutyl)-23,26-bis[(5-fluoro-1H-indol-3-yl)methyl]-14-[(4-hydroxyphenyl)methyl]-17-(1H-imidazol-5-ylmethyl)-8,29-dimethyl-7,13,16,19,22,25,28,31,34-nonaoxo-3,37-dithia-6,12,15,18,21,24,27,30,33-nonazatricyclo[37.3.1.08,12]tritetraconta-1(42),39(43),40-trien-20-yl]acetic acid	1700401: Inhibition of AlexaFluor647-tagged cyclic peptide binding to avi-tagged-biotinylated human PCSK9 measured after 2 hrs by Lance Streptavidin Europium based FRET assay	ki	0.0042	uM
2-[(8S,14S,17S,20S,23S,26S,29R,32S)-32-[4-(dimethylamino)butyl]-23,26-bis[(5-fluoro-1H-indol-3-yl)methyl]-17-(1H-imidazol-5-ylmethyl)-14-[(4-methoxyphenyl)methyl]-8,29-dimethyl-7,13,16,19,22,25,28,31,34-nonaoxo-3,37-dithia-6,12,15,18,21,24,27,30,33-nonazatricyclo[37.3.1.08,12]tritetraconta-1(42),39(43),40-trien-20-yl]acetic acid	1700401: Inhibition of AlexaFluor647-tagged cyclic peptide binding to avi-tagged-biotinylated human PCSK9 measured after 2 hrs by Lance Streptavidin Europium based FRET assay	ki	0.0042	uM
2-[(8S,14S,17S,20S,23S,26S,29R,32S)-32-(4-aminobutyl)-29-tert-butyl-23,26-bis[(5-fluoro-1H-indol-3-yl)methyl]-14-[(4-hydroxyphenyl)methyl]-17-(1H-imidazol-5-ylmethyl)-8-methyl-7,13,16,19,22,25,28,31,34-nonaoxo-3,37-dithia-6,12,15,18,21,24,27,30,33-nonazatricyclo[37.3.1.08,12]tritetraconta-1(42),39(43),40-trien-20-yl]acetic acid	1700401: Inhibition of AlexaFluor647-tagged cyclic peptide binding to avi-tagged-biotinylated human PCSK9 measured after 2 hrs by Lance Streptavidin Europium based FRET assay	ki	0.0042	uM
2-[(8S,14S,17S,20S,23S,26S,32S)-32-(4-aminobutyl)-23,26-bis[(5-fluoro-1H-indol-3-yl)methyl]-14-[(4-hydroxyphenyl)methyl]-17-(1H-imidazol-5-ylmethyl)-8-methyl-7,13,16,19,22,25,28,31,34-nonaoxo-3,37-dithia-6,12,15,18,21,24,27,30,33-nonazatricyclo[37.3.1.08,12]tritetraconta-1(42),39(43),40-trien-20-yl]acetic acid	1700401: Inhibition of AlexaFluor647-tagged cyclic peptide binding to avi-tagged-biotinylated human PCSK9 measured after 2 hrs by Lance Streptavidin Europium based FRET assay	ki	0.0043	uM
(2S,5S,8S,14S,32S,35S,38S,46Z,50S,54S)-32-(aminomethyl)-54-[(5-fluoro-1H-indol-3-yl)methyl]-5-[(1S)-1-methoxyethyl]-8-[(4-methoxyphenyl)methyl]-14,35-dimethyl-49-oxa-19,27-dithia-1,4,7,10,16,31,34,37,55-nonazahexacyclo[36.14.4.121,25.140,44.02,50.010,14]octapentaconta-21,23,25(58),40,42,44(57),46-heptaene-3,6,9,15,30,33,36,53,56-nonone	1813379: Inhibition of human PCSK9 using Alexa Fluor 674 as substrate incubated for 2 hrs by FRET assay	ki	0.0044	uM
(2S,5S,8S,14S,32S,35R,38S,46Z,50S,54S)-54-[(5-fluoro-1H-indol-3-yl)methyl]-5-[(1R)-1-hydroxyethyl]-8-[(4-methoxyphenyl)methyl]-14,32,35-trimethyl-49-oxa-19,27-dithia-1,4,7,10,16,31,34,37,55-nonazahexacyclo[36.14.4.121,25.140,44.02,50.010,14]octapentaconta-21,23,25(58),40,42,44(57),46-heptaene-3,6,9,15,30,33,36,53,56-nonone	1813379: Inhibition of human PCSK9 using Alexa Fluor 674 as substrate incubated for 2 hrs by FRET assay	ki	0.0047	uM
(2S,5S,8S,14S,32S,35R,38S,46Z,50S,54S)-54-[(5-fluoro-1H-indol-3-yl)methyl]-5-[(1R)-1-methoxyethyl]-8-[(4-methoxyphenyl)methyl]-14,32,35-trimethyl-49-oxa-19,27-dithia-1,4,7,10,16,31,34,37,55-nonazahexacyclo[36.14.4.121,25.140,44.02,50.010,14]octapentaconta-21,23,25(58),40,42,44(57),46-heptaene-3,6,9,15,30,33,36,53,56-nonone	1813379: Inhibition of human PCSK9 using Alexa Fluor 674 as substrate incubated for 2 hrs by FRET assay	ki	0.0048	uM
(4S)-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[2-[[(2R)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[[(2S)-1-[[(2S)-4-amino-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S,3S)-1-[[2-[[(2S)-1-[(2S)-2-[[(1R)-1-carboxy-2-sulfanylethyl]carbamoyl]pyrrolidin-1-yl]-4-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-4-methyl-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxo-3-sulfanylpropan-2-yl]amino]-2-oxoethyl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-amino-3-hydroxybutanoyl]amino]-3-methylbutanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoic acid	1933138: Binding affinity to human PCSK9	kd	0.0055	uM
3-[(2S,5S,8S,11S,19S)-19-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-(1H-imidazol-5-yl)propanoyl]amino]-3-methylbutanoyl]amino]-3-phenylpropanoyl]amino]-6-aminohexanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-11-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1,6-diamino-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]carbamoyl]-5-[(4-hydroxyphenyl)methyl]-8-(2-methylpropyl)-3,6,9,13,20-pentaoxo-1,4,7,10,14-pentazacycloicos-2-yl]propanoic acid	1817665: Binding affinity to human PCSK9 by surface plasmon resonance	kd	0.0060	uM
2-[(8S,14S,17S,20S,23S,26S,29R,32S)-32-(4-aminobutyl)-23,26-bis[(5-fluoro-1H-indol-3-yl)methyl]-14-[(4-hydroxyphenyl)methyl]-17-(1H-imidazol-5-ylmethyl)-8-methyl-7,13,16,19,22,25,28,31,34-nonaoxo-29-propan-2-yl-3,37-dithia-6,12,15,18,21,24,27,30,33-nonazatricyclo[37.3.1.08,12]tritetraconta-1(42),39(43),40-trien-20-yl]acetic acid	1700401: Inhibition of AlexaFluor647-tagged cyclic peptide binding to avi-tagged-biotinylated human PCSK9 measured after 2 hrs by Lance Streptavidin Europium based FRET assay	ki	0.0063	uM
3-[(2S,5S,8S,11S,15Z,20S)-20-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-(1H-imidazol-5-yl)propanoyl]amino]-3-methylbutanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-11-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1,6-diamino-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]carbamoyl]-5-[(4-hydroxyphenyl)methyl]-11,20-dimethyl-8-(2-methylpropyl)-3,6,9,21-tetraoxo-1,4,7,10-tetrazacyclohenicos-15-en-2-yl]propanoic acid	1817665: Binding affinity to human PCSK9 by surface plasmon resonance	kd	0.0070	uM
5-[5-[1-(4,4-dimethylpentyl)-5-naphthalen-2-ylimidazol-2-yl]-2-iodoimidazol-1-yl]-N-methylpentan-1-amine	1990773: Inhibition of His-tagged PCSK9 to recombinant LDLR (unknown origin) protein-protein interaction incubated for 2 hrs by fluorescence plate reader analysis	ic50	0.0070	uM
2-[(8S,14S,17S,20S,23S,26S,29R,32S)-32-[[[2-[2-(2-aminoethoxy)ethoxy]acetyl]amino]methyl]-23,26-bis[(5-fluoro-1H-indol-3-yl)methyl]-17-(1H-imidazol-5-ylmethyl)-14-[(4-methoxyphenyl)methyl]-8,29-dimethyl-7,13,16,19,22,25,28,31,34-nonaoxo-3,37-dithia-6,12,15,18,21,24,27,30,33-nonazatricyclo[37.3.1.08,12]tritetraconta-1(42),39(43),40-trien-20-yl]acetic acid	1700401: Inhibition of AlexaFluor647-tagged cyclic peptide binding to avi-tagged-biotinylated human PCSK9 measured after 2 hrs by Lance Streptavidin Europium based FRET assay	ki	0.0082	uM
5-[5-[1-(4,4-dimethylpentyl)-5-naphthalen-2-ylimidazol-2-yl]-2-ethynylimidazol-1-yl]-N-methylpentan-1-amine	1990773: Inhibition of His-tagged PCSK9 to recombinant LDLR (unknown origin) protein-protein interaction incubated for 2 hrs by fluorescence plate reader analysis	ic50	0.0090	uM
2-[(5R,8S,14S,17S,20S,23S,26S,32S)-5-carbamoyl-23,26-bis[(5-fluoro-1H-indol-3-yl)methyl]-14-[(4-hydroxyphenyl)methyl]-17-(1H-imidazol-5-ylmethyl)-32-[4-[3-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]propanoylamino]butyl]-8-methyl-7,13,16,19,22,25,28,31,34-nonaoxo-3,37-dithia-6,12,15,18,21,24,27,30,33-nonazatricyclo[37.3.1.08,12]tritetraconta-1(42),39(43),40-trien-20-yl]acetic acid	1700401: Inhibition of AlexaFluor647-tagged cyclic peptide binding to avi-tagged-biotinylated human PCSK9 measured after 2 hrs by Lance Streptavidin Europium based FRET assay	ki	0.0094	uM

CTD chemical–gene interactions

91 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	7
Aflatoxin B1	affects expression, decreases expression, increases methylation	6
Valproic Acid	affects cotreatment, decreases expression, affects expression	5
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	4
Cyclosporine	decreases expression, increases expression	4
Particulate Matter	increases abundance, affects cotreatment, decreases expression	3
bisphenol A	affects expression, affects cotreatment, increases expression	2
mercuric bromide	affects cotreatment, decreases expression	2
Acetaminophen	decreases expression	2
Estradiol	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
trichostatin A	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases secretion	1
9,10-dihydro-9,10-dihydroxybenzo(a)pyrene	decreases expression	1
perfluorooctanoic acid	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
sulindac sulfide	decreases expression	1
benazol P	affects expression	1
nivalenol	decreases expression	1
gallium arsenide	decreases expression	1
epigallocatechin gallate	increases expression	1

ChEMBL screening assays

202 unique, capped per target: 201 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3887820	Binding	AlphaLISA Assay: An in-vitro AlphaLISA assay (Perkin Elmer) was developed in order to quantitate the level of PCSK9 secreted into the cell culture media following compound treatment. To detect and measure PCSK9 protein an in-house generated	Substituted amide compounds
CHEMBL4221931	ADMET	Activation of PCSK9 (unknown origin) expressed in human HepG2 cells assessed as decrease in LDL uptake at 25 uM	Small molecule modulators of PCSK9 - A literature and patent overview. — Bioorg Med Chem Lett

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C7DD	Abcam A-549 PCSK9 KO	Cancer cell line	Male
CVCL_C7E3	Abcam HCT 116 PCSK9 KO	Cancer cell line	Male
CVCL_F1QC	HyCyte Hep-G2 KO-hPCSK9	Cancer cell line	Male

Clinical trials (associated diseases)

156 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00655265	PHASE4	COMPLETED	A Study of the Safety and Efficacy of Patients With Familial Hypercholesterolaemia Taking Colesevelam as add-on Therapy to Their Existing Medication
NCT00916643	PHASE4	COMPLETED	Low-Density Lipoprotein (LDL) Apheresis Using H.E.L.P. Therapy
NCT03331666	PHASE4	TERMINATED	Impact of LDL-cholesterol Lowering on Platelet Activation
NCT05465278	PHASE4	COMPLETED	Alirocumab and Plaque Burden In Familial Hypercholesterolaemia
NCT00730236	PHASE3	COMPLETED	A Safety and Efficacy Study of AEGR-733 to Treat Homozygous Familial Hypercholesterolemia (FH)
NCT01841684	PHASE3	TERMINATED	Efficacy and Tolerability of Anacetrapib Added to Ongoing Lipid-Lowering Therapy in Adult Participants With Homozygous Familial Hypercholesterolemia (HoFH) (MK-0859-042)
NCT02226198	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Rosuvastatin in Children and Adolescents With Homozygous Familial Hypercholesterolemia
NCT02434497	PHASE3	COMPLETED	A Study to Evaluate the Safety of Rosuvastatin in Children and Adolescents With Homozygous Familial Hypercholesterolemia
NCT02765841	PHASE3	WITHDRAWN	Evaluate the Efficacy and Safety of Lomitapide in Pediatric Patients With Homozygous Familial Hypercholesterolemia on Stable Lipid-lowering Therapy
NCT03156621	PHASE3	COMPLETED	Study in Participants With Homozygous Familial Hypercholesterolemia (HoFH)
NCT03399786	PHASE3	COMPLETED	Efficacy and Safety of Evinacumab in Patients With Homozygous Familial Hypercholesterolemia
NCT03409744	PHASE3	COMPLETED	Evaluate the Long-Term Safety and Efficacy of Evinacumab in Patients With Homozygous Familial Hypercholesterolemia
NCT03814187	PHASE3	COMPLETED	Trial to Assess the Effect of Long Term Dosing of Inclisiran in Subjects With High CV Risk and Elevated LDL-C
NCT03851705	PHASE3	COMPLETED	A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia (HoFH)
NCT04034485	PHASE3	COMPLETED	Phase 3 Study to Evaluate the Efficacy and Safety of LIB003 With Evolocumab in HoFH
NCT04233918	PHASE3	COMPLETED	Evaluate the Efficacy and Safety of Evinacumab in Pediatric Patients With Homozygous Familial Hypercholesterolemia
NCT05611528	PHASE3	COMPLETED	Safety and Effectiveness of Evinacumab for the Treatment of Homozygous Familial Hypercholesterolemia
NCT05682378	PHASE3	RECRUITING	Long-term Safety and Tolerability of Inclisiran in Participants With HeFH or HoFH Who Have Completed the Pediatric ORION-16, ORION-13, ORION-20, or ORION-19 Studies
NCT06712771	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Clinical Trial to Evaluate the Efficacy and Safety of VSA003 in Chinese HoFH Patients
NCT06723652	PHASE3	COMPLETED	A Multicenter, Randomized, Double-blind, Placebo-controlled Phase III Clinical Study Evaluating the Efficacy and Safety of SHR-1918 in Patients With Homozygous Familial Hypercholesterolemia
NCT07037771	PHASE3	RECRUITING	A Phase 3 Study of Zodasiran in Adolescent and Adult Subjects With Homozygous Familial Hypercholesterolemia (YOSEMITE)
NCT07473843	PHASE3	NOT_YET_RECRUITING	Study of Zodasiran in Adolescent Participants With Homozygous Familial Hypercholesterolemia
NCT00355615	PHASE3	COMPLETED	PLUTO: Pediatric Lipid-redUction Trial of rOsuvastatin
NCT00552097	PHASE3	COMPLETED	Effect of Ezetimibe Plus Simvastatin Versus Simvastatin Alone on Atherosclerosis in the Carotid Artery (ENHANCE)(P02578)
NCT00607373	PHASE3	COMPLETED	Study to Assess the Safety and Efficacy of ISIS 301012 (Mipomersen) in Homozygous Familial Hypercholesterolemia
NCT00694109	PHASE3	COMPLETED	An Open-label Extension Study to Assess the Long-term Safety and Efficacy of ISIS 301012 (Mipomersen) in Patients With Familial Hypercholesterolemia or Severe-Hypercholesterolemia
NCT00827606	PHASE3	COMPLETED	Atorvastatin Three Year Pediatric Study
NCT00943306	PHASE3	COMPLETED	Long Term, Follow-on Study of Lomitapide in Patients With Homozygous Familial Hypercholesterolemia
NCT01524289	PHASE3	COMPLETED	Study to Assess the Tolerability and Efficacy of Anacetrapib (MK-0859) Co-Administered With Statin in Participants With Heterozygous Familial Hypercholesterolemia (MK-0859-020)
NCT01813006	PHASE3	COMPLETED	Effect of Omega-3 Fatty Acid on Endothelial Function
NCT02624869	PHASE3	COMPLETED	Safety, Tolerability and Efficacy of Evolocumab (AMG 145) in Children With Inherited Elevated Low-density Lipoprotein Cholesterol (Familial Hypercholesterolemia)
NCT02748057	PHASE3	COMPLETED	A Clinical Trial to Assess the Long Term Safety and Tolerability of MK-0653H in Japanese Participants With Hypercholesterolemia (MK-0653H-833)
NCT03884452	PHASE3	COMPLETED	Ezetimibe (SCH 58235) Taken With Either Atorvastatin or Simvastatin in Participants With Familial Hypercholesterolemia (MK-0653-018)
NCT04798430	PHASE3	ENROLLING_BY_INVITATION	Long-term Efficacy and Safety of OLE LIB003 in HoFH, HeFH, and High-risk CVD Patients Requiring Further LDL-C Reduction
NCT05142722	PHASE3	COMPLETED	Randomized Study to Evaluate the Effect of Obicetrapib on Top of Maximum Tolerated Lipid-Modifying Therapies
NCT05238519	PHASE3	ACTIVE_NOT_RECRUITING	Improved Diagnosis of Familial Hypercholesterolemia Across the Northland (ID-FH)
NCT05425745	PHASE3	COMPLETED	Evaluate the Effect of Obicetrapib in Patients With HeFH on Top of Maximum Tolerated Lipid-Modifying Therapies.
NCT05952856	PHASE3	COMPLETED	A Study of Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) in Adults With Hypercholesterolemia (MK-0616-013) CORALreef Lipids
NCT05952869	PHASE3	COMPLETED	A Study of Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) in Adults With Heterozygous Familial Hypercholesterolemia (MK-0616-017/CORALreef HeFH)
NCT06005597	PHASE3	COMPLETED	Study of Obicetrapib & Ezetimibe Fixed Dose Combination on Top of Maximum Tolerated Lipid-Modifying Therapies