Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTUO98L)

• DTT Name: Angiopoietin-related protein 3 (ANGPTL3)
• Synonyms: UNQ153/PRO179; Angiopoietin-like protein 3; Angiopoietin-5; ANGPT5; ANG-5
• Gene Name: ANGPTL3
• DTT Type: Successful target; [1]
• BioChemical Class: Fibrinogen protein
• UniProt ID: ANGL3_HUMAN
• TTD ID: T53139
• Sequence:
  MFTIKLLLFIVPLVISSRIDQDNSSFDSLSPEPKSRFAMLDDVKILANGLLQLGHGLKDF
  VHKTKGQINDIFQKLNIFDQSFYDLSLQTSEIKEEEKELRRTTYKLQVKNEEVKNMSLEL
  NSKLESLLEEKILLQQKVKYLEEQLTNLIQNQPETPEHPEVTSLKTFVEKQDNSIKDLLQ
  TVEDQYKQLNQQHSQIKEIENQLRRTSIQEPTEISLSSKPRAPRTTPFLQLNEIRNVKHD
  GIPAECTTIYNRGEHTSGMYAIRPSNSQVFHVYCDVISGSPWTLIQHRIDGSQNFNETWE
  NYKYGFGRLDGEFWLGLEKIYSIVKQSNYVLRIELEDWKDNKHYIEYSFYLGNHETNYTL
  HLVAITGNVPNAIPENKDLVFSTWDHKAKGHFNCPEGYSGGWWWHDECGENNLNGKYNKP
  RAKSKPERRRGLSWKSQNGRLYSIKSTKMLIHPTDSESFE
• Function: Acts in part as a hepatokine that is involved in regulation of lipid and glucose metabolism. Proposed to play a role in the trafficking of energy substrates to either storage or oxidative tissues in response to food intake (By similarity). Has a stimulatory effect on plasma triglycerides (TG), which is achieved by suppressing plasma TG clearance via inhibition of LPL activity. The inhibition of LPL activity appears to be an indirect mechanism involving recruitment of proprotein convertases PCSK6 and FURIN to LPL leading to cleavage and dissociation of LPL from the cell surface; the function does not require ANGPTL3 proteolytic cleavage but seems to be mediated by the N-terminal domain, and is not inhibited by GPIHBP1. Can inhibit endothelial lipase, causing increased plasma levels of high density lipoprotein (HDL) cholesterol and phospholipids. Can bind to adipocytes to activate lipolysis, releasing free fatty acids and glycerol. Suppresses LPL specifically in oxidative tissues which is required to route very low density lipoprotein (VLDL)-TG to white adipose tissue (WAT) for storage in response to food; the function may involve cooperation with circulating, liver-derived ANGPTL8 and ANGPTL4 expression in WAT (By similarity). Contributes to lower plasma levels of low density lipoprotein (LDL)-cholesterol by a mechanism that is independent of the canonical pathway implicating APOE and LDLR. May stimulate hypothalamic LPL activity (By similarity).
• KEGG Pathway: Cholesterol metabolism (hsa04979)
• Reactome Pathway:
  NR1H2 & NR1H3 regulate gene expression linked to lipogenesis (R-HSA-9029558)
  Assembly of active LPL and LIPC lipase complexes (R-HSA-8963889)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Evinacumab	DMBLX7U	Hypercholesterolaemia	5C80.0	Approved	[2]

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AKCEA-ANGPTL3-LRX	DMR8W7Y	Cardiovascular disease	BA00-BE2Z	Phase 2	[3]
LNA043	DMDHVK8	Knee osteoarthritis	FA01	Phase 2	[4]

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2021
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Angiopoietin-like 3-derivative LNA043 for cartilage regeneration in osteoarthritis: a randomized phase 1 trial. Nat Med. 2022 Dec;28(12):2633-2645.