Target Information

Target General Infomation
Target ID
T62206
Former ID
TTDR01164
Target Name
Proprotein convertase subtilisin/kexin type 9
Gene Name
PCSK9
Synonyms
NARC-1; Neural apoptosis-regulated convertase 1; Proprotein convertase PC9; Subtilisin/kexin-like protease PC9; PCSK9
Target Type
Clinical Trial
Disease Coronary artery disease [ICD9: 410-414, 429.2; ICD10: I20-I25]
Chronic obstructive pulmonary disease [ICD9: 490-492, 494-496; ICD10: J40-J44, J47]
Cardiovascular disorder [ICD10: I00-I99]
Hypercholesterolemia [ICD10: E78]
Hyperlipidaemia [ICD9: 272.0-272.4; ICD10: E78]
Type 1 diabetes [ICD9: 250; ICD10: E10]
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 induceubiquitination 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.
BioChemical Class
Peptidase
UniProt ID
Q8NBP7
EC Number
EC 3.4.21.-
Sequence
MGTVSSRRSWWPLPLLLLLLLLLGPAGARAQEDEDGDYEELVLALRSEEDGLAEAPEHGT
TATFHRCAKDPWRLPGTYVVVLKEETHLSQSERTARRLQAQAARRGYLTKILHVFHGLLP
GFLVKMSGDLLELALKLPHVDYIEEDSSVFAQSIPWNLERITPPRYRADEYQPPDGGSLV
EVYLLDTSIQSDHREIEGRVMVTDFENVPEEDGTRFHRQASKCDSHGTHLAGVVSGRDAG
VAKGASMRSLRVLNCQGKGTVSGTLIGLEFIRKSQLVQPVGPLVVLLPLAGGYSRVLNAA
CQRLARAGVVLVTAAGNFRDDACLYSPASAPEVITVGATNAQDQPVTLGTLGTNFGRCVD
LFAPGEDIIGASSDCSTCFVSQSGTSQAAAHVAGIAAMMLSAEPELTLAELRQRLIHFSA
KDVINEAWFPEDQRVLTPNLVAALPPSTHGAGWQLFCRTVWSAHSGPTRMATAVARCAPD
EELLSCSSFSRSGKRRGERMEAQGGKLVCRAHNAFGGEGVYAIARCCLLPQANCSVHTAP
PAEASMGTRVHCHQQGHVLTGCSSHWEVEDLGTHKPPVLRPRGQPNQCVGHREASIHASC
CHAPGLECKVKEHGIPAPQEQVTVACEEGWTLTGCSALPGTSHVLGAYAVDNTCVVRSRD
VSTTGSTSEGAVTAVAICCRSRHLAQASQELQ
Drugs and Mode of Action
Drug(s) REGN-727 Drug Info Approved Heterozygous familial hypercholesterolemia; Clinical atherosclerotic cardiovascular disease [533123], [541842]
AMG 145 Drug Info Phase 3 Hypercholesterolemia [524291]
Bococizumab Drug Info Phase 3 Chronic obstructive pulmonary disease [525217], [542700]
PF-04950615 Drug Info Phase 3 Hypercholesterolemia [524502]
LY3015014 Drug Info Phase 2 Cardiovascular disorder [524347]
PCSK9 Adnectin Drug Info Phase 1 Cardiovascular disorder [525391]
SPC5001 Drug Info Phase 1 Hyperlipidaemia [551623]
Modulator AMG 145 Drug Info [532982]
PCSK9 Adnectin Drug Info [532837]
Inhibitor SPC5001 Drug Info [551623]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
WikiPathways PCSK9-mediated LDLR degradation
References
Ref 524291ClinicalTrials.gov (NCT01854918) Open Label Study of Long Term Evaluation Against LDL-C Trial-2. U.S. National Institutes of Health.
Ref 524347ClinicalTrials.gov (NCT01890967) A Study of LY3015014 in Participants With High Cholesterol. U.S. National Institutes of Health.
Ref 524502ClinicalTrials.gov (NCT01975376) The Evaluation of Bococizumab (PF-04950615;RN316) in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects. U.S. National Institutes of Health.
Ref 525217ClinicalTrials.gov (NCT02458287) Efficacy, Safety, Tolerability And Actual Use Study Of Bococizumab And An Autoinjector (Pre-Filled Pen) In Subjects With Hyperlipidemia Or Dyslipidemia.
Ref 525391Cholesterol-lowering blockbuster candidates speed into Phase III trials. Nat Rev Drug Discov. 2012 Nov;11(11):817-9. doi: 10.1038/nrd3879.
Ref 5331232014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
Ref 541842(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6744).
Ref 542700(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7730).
Ref 5516232011 Pipeline of Santaris Pharma.
Ref 531225A PCSK9-binding antibody that structurally mimics the EGF(A) domain of LDL-receptor reduces LDL cholesterol in vivo. J Lipid Res. 2011 Jan;52(1):78-86.
Ref 531924Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet. 2012 Jul 7;380(9836):29-36.
Ref 532578Phase 3 data for PCSK9 inhibitor wows. Nat Biotechnol. 2013 Dec;31(12):1057-8.
Ref 532837Pharmacologic profile of the Adnectin BMS-962476, a small protein biologic alternative to PCSK9 antibodies for low-density lipoprotein lowering. J Pharmacol Exp Ther. 2014 Aug;350(2):412-24.
Ref 532982PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015 Jan 24;385(9965):331-40.
Ref 532996The dyslipidaemia market. Nat Rev Drug Discov. 2014 Nov;13(11):807-8.
Ref 5331232014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
Ref 5516232011 Pipeline of Santaris Pharma.

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