Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT90XZ8)

• DTT Name: Voltage-gated sodium channel alpha Nav1.8 (SCN10A)
• Synonyms: hPN3; Voltage-gated sodium channel subunit alpha Nav1.8; Sodium channel protein type X subunit alpha; Sodium channel protein type 10 subunit alpha; Peripheral nerve sodium channel 3; PN3
• Gene Name: SCN10A
• DTT Type: Successful target; [1]
• BioChemical Class: Voltage-gated ion channel
• UniProt ID: SCNAA_HUMAN
• TTD ID: T43739
• Sequence:
  MEFPIGSLETNNFRRFTPESLVEIEKQIAAKQGTKKAREKHREQKDQEEKPRPQLDLKAC
  NQLPKFYGELPAELIGEPLEDLDPFYSTHRTFMVLNKGRTISRFSATRALWLFSPFNLIR
  RTAIKVSVHSWFSLFITVTILVNCVCMTRTDLPEKIEYVFTVIYTFEALIKILARGFCLN
  EFTYLRDPWNWLDFSVITLAYVGTAIDLRGISGLRTFRVLRALKTVSVIPGLKVIVGALI
  HSVKKLADVTILTIFCLSVFALVGLQLFKGNLKNKCVKNDMAVNETTNYSSHRKPDIYIN
  KRGTSDPLLCGNGSDSGHCPDGYICLKTSDNPDFNYTSFDSFAWAFLSLFRLMTQDSWER
  LYQQTLRTSGKIYMIFFVLVIFLGSFYLVNLILAVVTMAYEEQNQATTDEIEAKEKKFQE
  ALEMLRKEQEVLAALGIDTTSLHSHNGSPLTSKNASERRHRIKPRVSEGSTEDNKSPRSD
  PYNQRRMSFLGLASGKRRASHGSVFHFRSPGRDISLPEGVTDDGVFPGDHESHRGSLLLG
  GGAGQQGPLPRSPLPQPSNPDSRHGEDEHQPPPTSELAPGAVDVSAFDAGQKKTFLSAEY
  LDEPFRAQRAMSVVSIITSVLEELEESEQKCPPCLTSLSQKYLIWDCCPMWVKLKTILFG
  LVTDPFAELTITLCIVVNTIFMAMEHHGMSPTFEAMLQIGNIVFTIFFTAEMVFKIIAFD
  PYYYFQKKWNIFDCIIVTVSLLELGVAKKGSLSVLRSFRLLRVFKLAKSWPTLNTLIKII
  GNSVGALGNLTIILAIIVFVFALVGKQLLGENYRNNRKNISAPHEDWPRWHMHDFFHSFL
  IVFRILCGEWIENMWACMEVGQKSICLILFLTVMVLGNLVVLNLFIALLLNSFSADNLTA
  PEDDGEVNNLQVALARIQVFGHRTKQALCSFFSRSCPFPQPKAEPELVVKLPLSSSKAEN
  HIAANTARGSSGGLQAPRGPRDEHSDFIANPTVWVSVPIAEGESDLDDLEDDGGEDAQSF
  QQEVIPKGQQEQLQQVERCGDHLTPRSPGTGTSSEDLAPSLGETWKDESVPQVPAEGVDD
  TSSSEGSTVDCLDPEEILRKIPELADDLEEPDDCFTEGCIRHCPCCKLDTTKSPWDVGWQ
  VRKTCYRIVEHSWFESFIIFMILLSSGSLAFEDYYLDQKPTVKALLEYTDRVFTFIFVFE
  MLLKWVAYGFKKYFTNAWCWLDFLIVNISLISLTAKILEYSEVAPIKALRTLRALRPLRA
  LSRFEGMRVVVDALVGAIPSIMNVLLVCLIFWLIFSIMGVNLFAGKFWRCINYTDGEFSL
  VPLSIVNNKSDCKIQNSTGSFFWVNVKVNFDNVAMGYLALLQVATFKGWMDIMYAAVDSR
  EVNMQPKWEDNVYMYLYFVIFIIFGGFFTLNLFVGVIIDNFNQQKKKLGGQDIFMTEEQK
  KYYNAMKKLGSKKPQKPIPRPLNKFQGFVFDIVTRQAFDITIMVLICLNMITMMVETDDQ
  SEEKTKILGKINQFFVAVFTGECVMKMFALRQYYFTNGWNVFDFIVVVLSIASLIFSAIL
  KSLQSYFSPTLFRVIRLARIGRILRLIRAAKGIRTLLFALMMSLPALFNIGLLLFLVMFI
  YSIFGMSSFPHVRWEAGIDDMFNFQTFANSMLCLFQITTSAGWDGLLSPILNTGPPYCDP
  NLPNSNGTRGDCGSPAVGIIFFTTYIIISFLIMVNMYIAVILENFNVATEESTEPLSEDD
  FDMFYETWEKFDPEATQFITFSALSDFADTLSGPLRIPKPNRNILIQMDLPLVPGDKIHC
  LDILFAFTKNVLGESGELDSLKANMEEKFMATNLSKSSYEPIATTLRWKQEDISATVIQK
  AYRSYVLHRSMALSNTPCVPRAEEEAASLPDEGFVAFTANENCVLPDKSETASATSFPPS
  YESVTRGLSDRVNMRTSSSIQNEDEATSMELIAPGP
• Function: Tetrodotoxin-resistant channel that mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which sodium ions may pass in accordance with their electrochemical gradient. Plays a role in neuropathic pain mechanisms.
• Reactome Pathway: Interaction between L1 and Ankyrins (R-HSA-445095)

Molecular Interaction Atlas (MIA) of This DTT

6 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Bupivacaine	DM4PRFC	Anaesthesia	9A78.6	Approved	[2]
Proparacaine	DMLS39E	Anaesthesia	9A78.6	Approved	[2]
Rilpivirine	DMJ0QOW	Human immunodeficiency virus infection	1C62	Approved	[3]
Ropivacaine	DMSPJG2	Anaesthesia	9A78.6	Approved	[2]
Tetracaine	DM9J6C2	Spinal anesthesia	MB40.3	Approved	[4]
Tiapride	DMN6CAG	Alcohol dependence	6C40.2	Approved	[1]

5 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Conatumumab	DM2UOSN	Colorectal cancer	2B91.Z	Phase 2	[5]
VX-150	DMGDB21	Neuropathic pain	8E43.0	Phase 2	[6]
DSP-2230	DM0WTMD	Neuropathic pain	8E43.0	Phase 1	[7]
PF-01247324	DM93LMS	Pain	MG30-MG3Z	Phase 1	[8]
VX-128	DMC8J0G	Pain	MG30-MG3Z	Phase 1	[6]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Corus 1030	DMRVJ1A	Asthma	CA23	Discontinued in Phase 2	[9]
SIPATRIGINE	DMMQ4GC	Neurological disorder	6B60	Discontinued in Phase 2	[10]

12 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1-[5-(4-Chlorophenyl)-2-furoyl]piperazine	DM8NMAV	Discovery agent	N.A.	Investigative	[11]
5-(4-chlorophenyl)-N-(2-methylbenzyl)nicotinamide	DMV7HA1	Discovery agent	N.A.	Investigative	[12]
A-803467	DMWGRL8	Pain	MG30-MG3Z	Investigative	[13]
batrachotoxin	DMYH9SU	Discovery agent	N.A.	Investigative	[14]
BW-202W92	DMFKXMT	Discovery agent	N.A.	Investigative	[10]
CR-4892	DMXHIFZ	Pain	MG30-MG3Z	Investigative	[15]
N-(2-chlorobenzyl)-5-(4-chlorophenyl)nicotinamide	DM4IEWG	Discovery agent	N.A.	Investigative	[12]
N-benzyl-5-(4-chlorophenyl)nicotinamide	DM2XLHY	Discovery agent	N.A.	Investigative	[12]
PD-32577	DMBA15J	Discovery agent	N.A.	Investigative	[16]
SCH-725737	DM9YJI8	Discovery agent	N.A.	Investigative	[17]
SCH-725739	DMYKB0S	Discovery agent	N.A.	Investigative	[17]
veratridine	DMUF8JZ	Discovery agent	N.A.	Investigative	[18]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Asthma	CA23	Nasal and bronchial airway	9.89E-01	-0.16	-0.31

References

• [1] Emerging drugs in neuropathic pain. Expert Opin Emerg Drugs. 2007 Mar;12(1):113-26.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [3] Structures of muO-conotoxins from Conus marmoreus. I nhibitors of tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels in mammalian senso... J Biol Chem. 2004 Jun 11;279(24):25774-82.
• [4] Heterologous expression and functional analysis of rat Nav1.8 (SNS) voltage-gated sodium channels in the dorsal root ganglion neuroblastoma cell line ND7-23. Neuropharmacology. 2004 Mar;46(3):425-38.
• [5] Pathobiology of visceral pain: molecular mechanisms and therapeutic implications. II. Genetic approaches to pain therapy. Am J Physiol Gastrointest Liver Physiol. 2000 Apr;278(4):G507-12.
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.
• [8] Oral Administration of PF-01247324, a Subtype-Selective Nav1.8 Blocker, Reverses Cerebellar Deficits in a Mouse Model of Multiple Sclerosis. PLoS One. 2015; 10(3): e0119067.
• [9] Differential modulation of Nav1.7 and Nav1.8 peripheral nerve sodium channels by the local anesthetic lidocaine. Br J Pharmacol. 2004 Jun;142(3):576-84.
• [10] Oxadiazolylindazole sodium channel modulators are neuroprotective toward hippocampal neurones. J Med Chem. 2009 May 14;52(9):2694-707.
• [11] Discovery of potent furan piperazine sodium channel blockers for treatment of neuropathic pain. Bioorg Med Chem. 2008 Jun 15;16(12):6379-86.
• [12] Subtype-selective Na(v)1.8 sodium channel blockers: identification of potent, orally active nicotinamide derivatives. Bioorg Med Chem Lett. 2010 Nov 15;20(22):6812-5.
• [13] Sensory neuron voltage-gated sodium channels as analgesic drug targets. Curr Opin Neurobiol. 2008 Aug;18(4):383-8.
• [14] The poison Dart frog's batrachotoxin modulates Nav1.8. FEBS Lett. 2004 Nov 5;577(1-2):245-8.
• [15] 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: 585).
• [16] Synthesis and biological activity of substituted bis-(4-hydroxyphenyl)methanes as N-type calcium channel blockers. Bioorg Med Chem Lett. 1999 Aug 16;9(16):2447-52.
• [17] Novel steroidal saponins, Sch 725737 and Sch 725739, from a marine starfish, Novodinia antillensis. Bioorg Med Chem Lett. 2007 Oct 15;17(20):5543-7.
• [18] A comparison of the effects of veratridine on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels in isolated rat dorsal root ganglio... Pflugers Arch. 2008 Feb;455(5):929-38.