Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTHJTF7)

• DTT Name: Glycine transporter GlyT-1 (SLC6A9)
• Synonyms: Solute carrier family 6 member 9; Sodium- and chloride-dependent glycine transporter 1; Glycine type-1 transporter; Glycine transporter type 1; GlyT1; GlyT-1
• Gene Name: SLC6A9
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Neurotransmitter:sodium symporter
• UniProt ID: SC6A9_HUMAN
• TTD ID: T69685
• Sequence:
  MSGGDTRAAIARPRMAAAHGPVAPSSPEQVTLLPVQRSFFLPPFSGATPSTSLAESVLKV
  WHGAYNSGLLPQLMAQHSLAMAQNGAVPSEATKRDQNLKRGNWGNQIEFVLTSVGYAVGL
  GNVWRFPYLCYRNGGGAFMFPYFIMLIFCGIPLFFMELSFGQFASQGCLGVWRISPMFKG
  VGYGMMVVSTYIGIYYNVVICIAFYYFFSSMTHVLPWAYCNNPWNTHDCAGVLDASNLTN
  GSRPAALPSNLSHLLNHSLQRTSPSEEYWRLYVLKLSDDIGNFGEVRLPLLGCLGVSWLV
  VFLCLIRGVKSSGKVVYFTATFPYVVLTILFVRGVTLEGAFDGIMYYLTPQWDKILEAKV
  WGDAASQIFYSLGCAWGGLITMASYNKFHNNCYRDSVIISITNCATSVYAGFVIFSILGF
  MANHLGVDVSRVADHGPGLAFVAYPEALTLLPISPLWSLLFFFMLILLGLGTQFCLLETL
  VTAIVDEVGNEWILQKKTYVTLGVAVAGFLLGIPLTSQAGIYWLLLMDNYAASFSLVVIS
  CIMCVAIMYIYGHRNYFQDIQMMLGFPPPLFFQICWRFVSPAIIFFILVFTVIQYQPITY
  NHYQYPGWAVAIGFLMALSSVLCIPLYAMFRLCRTDGDTLLQRLKNATKPSRDWGPALLE
  HRTGRYAPTIAPSPEDGFEVQPLHPDKAQIPIVGSNGSSRLQDSRI
• Function: May play a role in regulation of glycine levels in NMDA receptor-mediated neurotransmission. Terminates the action of glycine by its high affinity sodium-dependent reuptake into presynaptic terminals.
• KEGG Pathway: Synaptic vesicle cycle (hsa04721)
• Reactome Pathway: Na+/Cl- dependent neurotransmitter transporters (R-HSA-442660)

Molecular Interaction Atlas (MIA) of This DTT

11 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BI 425809	DMH3XDR	Schizophrenia	6A20	Phase 3	[2]
Iclepertin	DM83JCK	Schizophrenia	6A20	Phase 3	[3]
R1678	DM4K9WH	Schizophrenia	6A20	Phase 3	[1]
AMG 747	DMWPGB8	Schizophrenia	6A20	Phase 2	[4]
ORG-25935	DMWN2EC	Psychotic disorder	6A20-6A25	Phase 2	[5]
PF-3463275	DMO02LU	Schizophrenia	6A20	Phase 2	[4]
ALX-5407	DMLJWPN	Schizophrenia	6A20	Phase 1	[6]
DCCCyB	DMQ8ACY	Schizophrenia	6A20	Phase 1	[7]
GlyT1 PET radiotracers	DMCKZUT	Schizophrenia	6A20	Phase 1	[8]
JNJ-17305600	DMMI4XR	Schizophrenia	6A20	Phase 1	[9]
MK-2637	DMUHOJP	Schizophrenia	6A20	Phase 1	[10]

33 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID29338548-Compound-13	DMDJFUX	Schizophrenia	6A20	Patented	[11]
PMID29338548-Compound-14	DMXIO9A	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-15	DM6J0Z8	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-16	DMQNVUB	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-17	DMFXCPQ	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-18	DM0XA3D	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-19	DMKHTE1	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-20	DMZ3EHV	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-21	DMRTBKC	Schizophrenia	6A20	Patented	[11]
PMID29338548-Compound-22	DMT3AL5	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-23	DMTA3D8	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-24	DMWRGOX	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-25	DM83LWC	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-26	DMT2D5H	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-27	DMNW37Y	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-28	DMNBT3K	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-29	DMUGC53	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-30	DM8JK2D	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-31	DMWMPE2	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-33	DM4Q5SW	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-34	DM839NQ	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-36	DMG675B	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-37	DMAM0US	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-38	DM6BKQ8	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-39	DM69Y7R	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-40	DMLAHC1	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-41	DM2L7ES	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-44	DMJYQLC	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-45	DMO4JYK	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-46	DMRKIA1	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-47	DMHBOK6	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-48	DMDRJHO	N. A.	N. A.	Patented	[11]
PMID29338548-Compound-49	DM1NJ3U	N. A.	N. A.	Patented	[11]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GSK1018921	DM7ACJ4	Schizophrenia	6A20	Discontinued in Phase 1	[12]

6 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Org-24461	DMCMS7V	Schizophrenia	6A20	Preclinical	[13]
Organon	DMERWUC	Schizophrenia	6A20	Preclinical	[13]
Organon-2	DM46QXZ	Schizophrenia	6A20	Preclinical	[13]
Organon-3	DM07EU4	Schizophrenia	6A20	Preclinical	[13]
SSR-103800	DM84EOW	Schizophrenia	6A20	Preclinical	[13]
SSR-504734	DMQTR4I	Schizophrenia	6A20	Preclinical	[13]

10 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AS-1522489-00	DM7A8PX	Dementia	6D80-6D86	Investigative	[9]
GSK931145	DMIDQ8B	Discovery agent	N.A.	Investigative	[9]
LY2365109	DMBFLOJ	Discovery agent	N.A.	Investigative	[9]
RO-4840700	DMC0V25	Schizophrenia	6A20	Investigative	[9]
[35S]ACPPB	DMVUEYM	Discovery agent	N.A.	Investigative	[14]
[3H](R)-NPTS	DMRPS2X	Discovery agent	N.A.	Investigative	[15]
[3H]GSK931145	DMU6A3W	Discovery agent	N.A.	Investigative	[16]
[3H]N-methyl-SSR504734	DMX4RJ8	Discovery agent	N.A.	Investigative	[9]
[3H]NFPS	DM6PO49	Discovery agent	N.A.	Investigative	[9]
[3H]SB-733993	DMUS7EH	Discovery agent	N.A.	Investigative	[16]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Schizophrenia	6A20	Pre-frontal cortex	4.94E-01	-0.09	-0.34
Schizophrenia	6A20	Superior temporal cortex	1.64E-01	-0.03	-0.17

The Drug Transporter (DTP) Role of This DTT

• DTT DTP Name: Sodium- and chloride-dependent glycine transporter 1 (SLC6A9) DTP Info
• Gene Name: SLC6A9

1 Approved Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Glycine	DMIOZ29	Allergic rhinitis	CA08.0	Approved	[17]

1 Investigative Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
sarcosine	DMIVGOR	Discovery agent	N.A.	Investigative	[18]

References

• [1] Clinical pipeline report, company report or official report of Roche (2009).
• [2] Efficacy and safety of the novel glycine transporter inhibitor BI 425809 once daily in patients with schizophrenia: a double-blind, randomised, placebo-controlled phase 2 study. Lancet Psychiatry. 2021 Mar;8(3):191-201.
• [3] Effects of the Glycine Transporter-1 Inhibitor Iclepertin (BI 425809) on Sensory Processing, Neural Network Function, and Cognition in Animal Models Related to Schizophrenia. J Pharmacol Exp Ther. 2022 Aug;382(2):223-232.
• [4] Glycine transporters as novel therapeutic targets in schizophrenia, alcohol dependence and pain. Nat Rev Drug Discov. 2013 Nov;12(11):866-85.
• [5] The selective glycine uptake inhibitor org 25935 as an adjunctive treatment to atypical antipsychotics in predominant persistent negative symptoms of schizophrenia: results from the GIANT trial. J Clin Psychopharmacol. 2014 Apr;34(2):190-8.
• [6] ALX 5407: a potent, selective inhibitor of the hGlyT1 glycine transporter. Mol Pharmacol. 2001 Dec;60(6):1414-20.
• [7] Identification of an Orally Bioavailable, Potent, and Selective Inhibitor of GlyT1. ACS Med Chem Lett. 2010 October 14; 1(7): 350-354.
• [8] Glycine Transport Inhibitors for the Treatment of Schizophrenia. Open Med Chem J. 2010; 4: 10-19.
• [9] 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: 935).
• [10] Characterization of the novel GlyT1 PET tracer [18F]MK-6577 in humans. Synapse. 2015 Jan;69(1):33-40.
• [11] Glycine transporter-1 inhibitors: a patent review (2011-2016).Expert Opin Ther Pat. 2018 Mar;28(3):197-210.
• [12] Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
• [13] The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct;12(10):904-22.
• [14] A novel radioligand for glycine transporter 1: characterization and use in autoradiographic and in vivo brain occupancy studies. Nucl Med Biol. 2008 Apr;35(3):315-25.
• [15] [3H]-(R)-NPTS, a radioligand for the type 1 glycine transporter. Bioorg Med Chem Lett. 2003 Apr 7;13(7):1291-2.
• [16] Pharmacological characterisation of the GlyT-1 glycine transporter using two novel radioligands. Neuropharmacology. 2010 Nov;59(6):558-65.
• [17] Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans. Hum Genet. 2016 Nov;135(11):1263-1268.
• [18] Glycine is taken up through GLYT1 and GLYT2 transporters into mouse spinal cord axon terminals and causes vesicular and carrier-mediated release of its proposed co-transmitter GABA. J Neurochem. 2001 Mar;76(6):1823-32.