Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTKP2SU)

• DTT Name: Transient receptor potential cation channel V4 (TRPV4)
• Synonyms: Vanilloid receptor-related osmotically-activated channel; Vanilloid receptor-like protein 2; Vanilloid receptor-like channel 2; VROAC; VRL2; VRL-2; VR-OAC; TrpV4; Transient receptor potential protein 12; Transient receptor potential cation channel subfamily V member 4; TRP12; Osm-9-like TRP channel 4; OTRPC4
• Gene Name: TRPV4
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Transient receptor potential catioin channel
• UniProt ID: TRPV4_HUMAN
• TTD ID: T64213
• Sequence:
  MADSSEGPRAGPGEVAELPGDESGTPGGEAFPLSSLANLFEGEDGSLSPSPADASRPAGP
  GDGRPNLRMKFQGAFRKGVPNPIDLLESTLYESSVVPGPKKAPMDSLFDYGTYRHHSSDN
  KRWRKKIIEKQPQSPKAPAPQPPPILKVFNRPILFDIVSRGSTADLDGLLPFLLTHKKRL
  TDEEFREPSTGKTCLPKALLNLSNGRNDTIPVLLDIAERTGNMREFINSPFRDIYYRGQT
  ALHIAIERRCKHYVELLVAQGADVHAQARGRFFQPKDEGGYFYFGELPLSLAACTNQPHI
  VNYLTENPHKKADMRRQDSRGNTVLHALVAIADNTRENTKFVTKMYDLLLLKCARLFPDS
  NLEAVLNNDGLSPLMMAAKTGKIGIFQHIIRREVTDEDTRHLSRKFKDWAYGPVYSSLYD
  LSSLDTCGEEASVLEILVYNSKIENRHEMLAVEPINELLRDKWRKFGAVSFYINVVSYLC
  AMVIFTLTAYYQPLEGTPPYPYRTTVDYLRLAGEVITLFTGVLFFFTNIKDLFMKKCPGV
  NSLFIDGSFQLLYFIYSVLVIVSAALYLAGIEAYLAVMVFALVLGWMNALYFTRGLKLTG
  TYSIMIQKILFKDLFRFLLVYLLFMIGYASALVSLLNPCANMKVCNEDQTNCTVPTYPSC
  RDSETFSTFLLDLFKLTIGMGDLEMLSSTKYPVVFIILLVTYIILTFVLLLNMLIALMGE
  TVGQVSKESKHIWKLQWATTILDIERSFPVFLRKAFRSGEMVTVGKSSDGTPDRRWCFRV
  DEVNWSHWNQNLGIINEDPGKNETYQYYGFSHTVGRLRRDRWSSVVPRVVELNKNSNPDE
  VVVPLDSMGNPRCDGHQQGYPRKWRTDDAPL
• Function: Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity. Activation by exposure to hypotonicity within the physiological range exhibits an outward rectification. Also activated by heat, low pH, citrate and phorbol esters. Increase of intracellular Ca(2+) potentiates currents. Channel activity seems to be regulated by a calmodulin-dependent mechanism with a negative feedback mechanism. Promotes cell-cell junction formation in skin keratinocytes and plays an important role in the formation and/or maintenance of functional intercellular barriers (By similarity). Acts as a regulator of intracellular Ca(2+) in synoviocytes. Plays an obligatory role as a molecular component in the nonselective cation channel activation induced by 4-alpha-phorbol 12,13-didecanoate and hypotonic stimulation in synoviocytes and also regulates production of IL-8. Together with PKD2, forms mechano- and thermosensitive channels in cilium. Negatively regulates expression of PPARGC1A, UCP1, oxidative metabolism and respiration in adipocytes (By similarity). Regulates expression of chemokines and cytokines related to proinflammatory pathway in adipocytes (By similarity). Together with AQP5, controls regulatory volume decrease in salivary epithelial cells (By similarity). Required for normal development and maintenance of bone and cartilage.
• KEGG Pathway: Inflammatory mediator regulation of TRP channels (hsa04750)
• Reactome Pathway: TRP channels (R-HSA-3295583)

Molecular Interaction Atlas (MIA) of This DTT

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GSK2798745	DM7V96W	Heart failure	BD10-BD13	Phase 2	[2]
phorbol 12-myristate 13-acetate	DMJWD62	Acute myeloid leukaemia	2A60	Phase 2	[1]

15 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
4-Pyridin-2-yl-piperazine-1-carboxylic acid amide	DMFC8Q4	Discovery agent	N.A.	Investigative	[3]
4alpha-PDD	DMTSPLX	Discovery agent	N.A.	Investigative	[1]
4alpha-PDH	DMUOLES	Discovery agent	N.A.	Investigative	[4]
5'-iodoresiniferatoxin	DMQINY5	Discovery agent	N.A.	Investigative	[3]
5,6-epoxyeicosatrienoic acid	DMXTYCU	Discovery agent	N.A.	Investigative	[5]
bisandrographolide	DMRSKGC	Discovery agent	N.A.	Investigative	[6]
CAPSAZEPINE	DM4ATCI	Discovery agent	N.A.	Investigative	[7]
citric acid	DM80YI7	Discovery agent	N.A.	Investigative	[8]
GSK1016790A	DMDHZR1	Discovery agent	N.A.	Investigative	[9]
GSK2193874	DMY2XV3	Discovery agent	N.A.	Investigative	[10]
HC067047	DMIXY1O	Discovery agent	N.A.	Investigative	[11]
Pyrrolidin-1-yl-thiourea	DMYNZXC	Discovery agent	N.A.	Investigative	[3]
RN1734	DMA3ZXM	Discovery agent	N.A.	Investigative	[12]
RN1747	DMIPZTM	Discovery agent	N.A.	Investigative	[12]
SC-0030	DMD2WEQ	Discovery agent	N.A.	Investigative	[13]

References

• [1] Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives. J Biol Chem. 2002 Apr 19;277(16):13569-77.
• [2] Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.
• [3] N-4-methansulfonamidobenzyl-N'-2-substituted-4-tert-butyl-benzyl thioureas as potent vanilloid receptor antagonistic ligands. Bioorg Med Chem Lett. 2004 Apr 5;14(7):1693-6.
• [4] Modulation of the transient receptor potential vanilloid channel TRPV4 by 4alpha-phorbol esters: a structure-activity study. J Med Chem. 2009 May 14;52(9):2933-9.
• [5] Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature. 2003 Jul 24;424(6947):434-8.
• [6] Bisandrographolide from Andrographis paniculata activates TRPV4 channels. J Biol Chem. 2006 Oct 6;281(40):29897-904.
• [7] Chain-branched acyclic phenethylthiocarbamates as vanilloid receptor antagonists. Bioorg Med Chem Lett. 2003 May 5;13(9):1549-52.
• [8] Impaired pressure sensation in mice lacking TRPV4. J Biol Chem. 2003 Jun 20;278(25):22664-8.
• [9] N-((1S)-1-{[4-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide (GSK1016790A), a novel and potent transient receptor potential vanilloid 4 channel agonist induces urinary bladder contraction and hyperactivity: Part I. J Pharmacol Exp Ther. 2008 Aug;326(2):432-42.
• [10] An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure. Sci Transl Med. 2012 Nov 7;4(159):159ra148.
• [11] Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis. Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):19084-9.
• [12] Identification and characterization of novel TRPV4 modulators. Biochem Biophys Res Commun. 2009 Nov 20;389(3):490-4.
• [13] Novel non-vanilloid VR1 antagonist of high analgesic effects and its structural requirement for VR1 antagonistic effects. Bioorg Med Chem Lett. 2003 Dec 15;13(24):4389-93.