Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTBRG7E)

• DTT Name: Proprotein convertase subtilisin/kexin type 9 (PCSK9)
• Synonyms: Subtilisin/kexin-like protease PC9; Proprotein convertase 9; PC9; Neural apoptosis-regulated convertase 1; NARC1; NARC-1
• Gene Name: PCSK9
• DTT Type: Successful target; [1]
• BioChemical Class: Peptidase
• UniProt ID: PCSK9_HUMAN
• TTD ID: T62206
• EC Number: EC 3.4.21.-
• Sequence:
  MGTVSSRRSWWPLPLLLLLLLLLGPAGARAQEDEDGDYEELVLALRSEEDGLAEAPEHGT
  TATFHRCAKDPWRLPGTYVVVLKEETHLSQSERTARRLQAQAARRGYLTKILHVFHGLLP
  GFLVKMSGDLLELALKLPHVDYIEEDSSVFAQSIPWNLERITPPRYRADEYQPPDGGSLV
  EVYLLDTSIQSDHREIEGRVMVTDFENVPEEDGTRFHRQASKCDSHGTHLAGVVSGRDAG
  VAKGASMRSLRVLNCQGKGTVSGTLIGLEFIRKSQLVQPVGPLVVLLPLAGGYSRVLNAA
  CQRLARAGVVLVTAAGNFRDDACLYSPASAPEVITVGATNAQDQPVTLGTLGTNFGRCVD
  LFAPGEDIIGASSDCSTCFVSQSGTSQAAAHVAGIAAMMLSAEPELTLAELRQRLIHFSA
  KDVINEAWFPEDQRVLTPNLVAALPPSTHGAGWQLFCRTVWSAHSGPTRMATAVARCAPD
  EELLSCSSFSRSGKRRGERMEAQGGKLVCRAHNAFGGEGVYAIARCCLLPQANCSVHTAP
  PAEASMGTRVHCHQQGHVLTGCSSHWEVEDLGTHKPPVLRPRGQPNQCVGHREASIHASC
  CHAPGLECKVKEHGIPAPQEQVTVACEEGWTLTGCSALPGTSHVLGAYAVDNTCVVRSRD
  VSTTGSTSEGAVTAVAICCRSRHLAQASQELQ
• 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.
• KEGG Pathway: Cholesterol metabolism (hsa04979)
• Reactome Pathway:
  VLDLR internalisation and degradation (R-HSA-8866427)
  Post-translational protein phosphorylation (R-HSA-8957275)
  LDL clearance (R-HSA-8964038)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Evolocumab	DMNSAND	Heterozygous familial hypercholesterolemia	5C80.00	Approved	[2]
REGN-727	DM87XSN	Familial hypercholesterolemia	5C80.00	Approved	[1]

10 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AMG 145	DMG324Y	Hypercholesterolaemia	5C80.0	Phase 3	[3]
Bococizumab	DM2OBNW	Chronic obstructive pulmonary disease	CA22	Phase 3	[4]
LIB003	DMVP8WU	Hypercholesterolaemia	5C80.0	Phase 3	[5]
PF-04950615	DM0TWCY	Hypercholesterolaemia	5C80.0	Phase 3	[6]
LY3015014	DMFMKQ3	Cardiovascular disease	BA00-BE2Z	Phase 2	[4]
MK-0616	DMVGMNC	Hypercholesterolaemia	5C80.0	Phase 2	[7]
AZD0780	DMAFPNI	Elevated Lipoprotein(a)	5C80.1	Phase 1	[8]
NNC-0385-0434	DMBII8C	Hypercholesterolaemia	5C80.0	Phase 1	[9]
PCSK9 Adnectin	DMH86KO	Cardiovascular disease	BA00-BE2Z	Phase 1	[10]
SPC5001	DMUPQ70	Hyperlipidaemia	5C80	Phase 1	[11]

1 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1D05	DMGSQTK	Coronary artery disease	BA80	Investigative	[12]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Coronary artery disease	BA80-BA8Z	Peripheral blood	9.13E-01	-0.13	-0.62
Familial hypercholesterolemia	5A11	Whole blood	4.82E-02	-0.07	-0.3
Chronic obstructive pulmonary disease	CA23	Lung tissue	7.63E-01	-0.01	-0.03
Chronic obstructive pulmonary disease	CA23	Small airway epithelium	5.44E-01	0.02	0.07

References

• [1] Effect 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.
• [2] Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May 4;376(18):1713-1722.
• [3] PCSK9 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.
• [4] The dyslipidaemia market. Nat Rev Drug Discov. 2014 Nov;13(11):807-8.
• [5] ClinicalTrials.gov (NCT05234775) Cross-Over Study to Compare the Pharmacokinetics and Pharmacodynamics of LIB003 Process 1 and Process 2 Drug Product in Subjects With or Without Statin Therapy. U.S.National Institutes of Health.
• [6] Phase 3 data for PCSK9 inhibitor wows. Nat Biotechnol. 2013 Dec;31(12):1057-8.
• [7] Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616. J Am Coll Cardiol. 2023 Apr 25;81(16):1553-1564.
• [8] Clinical pipeline report, company report or official report of AstraZeneca
• [9] ClinicalTrials.gov (NCT04058834) A First Human Dose Trial Investigating Safety, Tolerability and Pharmacokinetics of Single Doses of NNC0385-0434 in Healthy Subjects and Patients With Hypercholesterolaemia. U.S.National Institutes of Health.
• [10] Pharmacologic 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.
• [11] 2011 Pipeline of Santaris Pharma.
• [12] A 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.