Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT23PYC)

• DTT Name: Soluble guanylate cyclase (GCS)
• Synonyms: GUCY1; GUCS; GUC1; GCS
• Gene Name: GUCY1A1
• DTT Type: Successful target; [1]
• BioChemical Class: Phosphorus-oxygen lyase
• UniProt ID: GCYA1_HUMAN ; GCYB1_HUMAN
• TTD ID: T57680
• Sequence:
  MFCTKLKDLKITGECPFSLLAPGQVPNESSEEAAGSSESCKATVPICQDIPEKNIQESLP
  QRKTSRSRVYLHTLAESICKLIFPEFERLNVALQRTLAKHKIKESRKSLEREDFEKTIAE
  QAVAAGVPVEVIKESLGEEVFKICYEEDENILGVVGGTLKDFLNSFSTLLKQSSHCQEAG
  KRGRLEDASILCLDKEDDFLHVYYFFPKRTTSLILPGIIKAAAHVLYETEVEVSLMPPCF
  HNDCSEFVNQPYLLYSVHMKSTKPSLSPSKPQSSLVIPTSLFCKTFPFHFMFDKDMTILQ
  FGNGIRRLMNRRDFQGKPNFEEYFEILTPKINQTFSGIMTMLNMQFVVRVRRWDNSVKKS
  SRVMDLKGQMIYIVESSAILFLGSPCVDRLEDFTGRGLYLSDIPIHNALRDVVLIGEQAR
  AQDGLKKRLGKLKATLEQAHQALEEEKKKTVDLLCSIFPCEVAQQLWQGQVVQAKKFSNV
  TMLFSDIVGFTAICSQCSPLQVITMLNALYTRFDQQCGELDVYKVETIGDAYCVAGGLHK
  ESDTHAVQIALMALKMMELSDEVMSPHGEPIKMRIGLHSGSVFAGVVGVKMPRYCLFGNN
  VTLANKFESCSVPRKINVSPTTYRLLKDCPGFVFTPRSREELPPNFPSEIPGICHFLDAY
  QQGTNSKPCFQKKDVEDGNANFLGKASGID
• Function: Probably plays a specific functional role in the rods and/or cones of photoreceptors. It may be the enzyme involved in the resynthesis of cGMP required for recovery of the dark state after phototransduction.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  cGMP-PKG signaling pathway (hsa04022)
  Vascular smooth muscle contraction (hsa04270)
  Gap junction (hsa04540)
  Platelet activation (hsa04611)
  Circadian entrainment (hsa04713)
  Long-term depression (hsa04730)
  Oxytocin signaling pathway (hsa04921)
  Renin secretion (hsa04924)
  Salivary secretion (hsa04970)
• Reactome Pathway:
  Smooth Muscle Contraction (R-HSA-445355)
  Nitric oxide stimulates guanylate cyclase (R-HSA-392154)

Molecular Interaction Atlas (MIA) of This DTT

3 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Nitric Oxide	DM1RBYG	Hypertension	BA00-BA04	Approved	[2]
Nitroglycerin	DMQ2491	Angina pectoris	BA40	Approved	[1]
Sodium nitroprusside	DMGA9X0	Hypertension	BA00-BA04	Approved	[3]

5 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CTI-1601	DMM4JMB	Friedreich's ataxia	8A03.10	Phase 2	[4]
CY6463	DM84AVQ	Alzheimer disease	8A20	Phase 2	[5]
IW-1973	DMK2T7J	Heart failure	BD10-BD13	Phase 2	[6]
MK-5475	DMIIZ4R	Pulmonary arterial hypertension	BB01.0	Phase 2	[7]
Runcaciguat	DMCFTTN	Chronic kidney disease	GB61	Phase 2	[8]

1 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(5-(1-benzyl-1H-indazol-3-yl)furan-2-yl)methanol	DM15P2G	Discovery agent	N.A.	Investigative	[1]

References

• [1] Activators of soluble guanylate cyclase for the treatment of male erectile dysfunction. Int J Impot Res. 2002 Feb;14(1):8-14.
• [2] Nitric oxide and nitrovasodilators: similarities, differences, and interactions. Am J Cardiol. 1996 May 30;77(13):2C-7C.
• [3] Stimulators and activators of soluble guanylate cyclase: review and potential therapeutic indications.Crit Care Res Pract.2012;2012:290805.
• [4] The CNS-Penetrant Soluble Guanylate Cyclase Stimulator CY6463 Reveals its Therapeutic Potential in Neurodegenerative Diseases. Front Pharmacol. 2021 May 24;12:656561.
• [5] First-in-human trial to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of zagociguat (CY6463), a CNS-penetrant soluble guanylyl cyclase stimulator. Clin Transl Sci. 2023 Aug;16(8):1381-1395.
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] Effects of an inhaled soluble guanylate cyclase (sGC) stimulator MK-5475 in pulmonary arterial hypertension (PAH). Respir Med. 2023 Jan;206:107065.
• [8] Runcaciguat, a novel soluble guanylate cyclase activator, shows renoprotection in hypertensive, diabetic, and metabolic preclinical models of chronic kidney disease. Naunyn Schmiedebergs Arch Pharmacol. 2021 Dec;394(12):2363-2379.