Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTNIZ2B)

• DTT Name: PCSK9 messenger RNA (PCSK9 mRNA)
• Synonyms: Subtilisin/kexin-like protease PC9 (mRNA); Proprotein convertase subtilisin/kexin type 9 (mRNA); Proprotein convertase 9 (mRNA); PSEC0052 (mRNA); PC9 (mRNA); Neural apoptosis-regulated convertase 1 (mRNA); NARC1 (mRNA); NARC-1 (mRNA)
• Gene Name: PCSK9
• DTT Type: Clinical trial target; [1]
• BioChemical Class: mRNA target
• UniProt ID: PCSK9_HUMAN
• TTD ID: T86652
• EC Number: EC 3.4.21.-
• Sequence:
  MGTVSSRRSWWPLPLLLLLLLLLGPAGARAQEDEDGDYEELVLALRSEEDGLAEAPEHGT
  TATFHRCAKDPWRLPGTYVVVLKEETHLSQSERTARRLQAQAARRGYLTKILHVFHGLLP
  GFLVKMSGDLLELALKLPHVDYIEEDSSVFAQSIPWNLERITPPRYRADEYQPPDGGSLV
  EVYLLDTSIQSDHREIEGRVMVTDFENVPEEDGTRFHRQASKCDSHGTHLAGVVSGRDAG
  VAKGASMRSLRVLNCQGKGTVSGTLIGLEFIRKSQLVQPVGPLVVLLPLAGGYSRVLNAA
  CQRLARAGVVLVTAAGNFRDDACLYSPASAPEVITVGATNAQDQPVTLGTLGTNFGRCVD
  LFAPGEDIIGASSDCSTCFVSQSGTSQAAAHVAGIAAMMLSAEPELTLAELRQRLIHFSA
  KDVINEAWFPEDQRVLTPNLVAALPPSTHGAGWQLFCRTVWSAHSGPTRMATAVARCAPD
  EELLSCSSFSRSGKRRGERMEAQGGKLVCRAHNAFGGEGVYAIARCCLLPQANCSVHTAP
  PAEASMGTRVHCHQQGHVLTGCSSHWEVEDLGTHKPPVLRPRGQPNQCVGHREASIHASC
  CHAPGLECKVKEHGIPAPQEQVTVACEEGWTLTGCSALPGTSHVLGAYAVDNTCVVRSRD
  VSTTGSTSEGAVTAVAICCRSRHLAQASQELQ
• Function: 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. Crucial player in the regulation of plasma cholesterol homeostasis.
• 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

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Inclisiran	DMP3YTE	Familial hypercholesterolemia	5C80.00	Approved	[2]

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AZD8233	DMBT2D2	Cardiovascular disease	BA00-BE2Z	Phase 2	[3]
MPSK3169A	DMMRYEK	Cardiovascular disease	BA00-BE2Z	Phase 2	[1]

2 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ALN-PCS	DMCJMOS	Hypercholesterolaemia	5C80.0	Preclinical	[4]
BMS-PCSK9	DMRCMEK	Coronary artery disease	BA80	Preclinical	[5]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Familial hypercholesterolemia	5A11	Whole blood	4.82E-02	-0.07	-0.3
Coronary artery disease	BA80-BA8Z	Peripheral blood	9.13E-01	-0.13	-0.62

References

• [1] URL: 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. (Target id: 2388).
• [2] FDA Approved Drug Products from FDA Official Website. 2021. Application Number: 214012.
• [3] AZD8233 antisense oligonucleotide targeting PCSK9 does not prolong QT interval. Br J Clin Pharmacol. 2022 Nov;88(11):4839-4844.
• [4] Clinical pipeline report, company report or official report of Alnylam Pharmaceuticals, Inc (2011).
• [5] Clinical pipeline report, company report or official report of ISIS Pharmaceuticals (2011).