Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTTV8EJ)

• DTT Name: Serine/threonine-protein kinase Sgk1 (SGK1)
• Synonyms: Serum/glucocorticoid-regulated kinase 1; SGK1
• Gene Name: SGK1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: SGK1_HUMAN
• TTD ID: T64682
• EC Number: EC 2.7.11.1
• Sequence:
  MTVKTEAAKGTLTYSRMRGMVAILIAFMKQRRMGLNDFIQKIANNSYACKHPEVQSILKI
  SQPQEPELMNANPSPPPSPSQQINLGPSSNPHAKPSDFHFLKVIGKGSFGKVLLARHKAE
  EVFYAVKVLQKKAILKKKEEKHIMSERNVLLKNVKHPFLVGLHFSFQTADKLYFVLDYIN
  GGELFYHLQRERCFLEPRARFYAAEIASALGYLHSLNIVYRDLKPENILLDSQGHIVLTD
  FGLCKENIEHNSTTSTFCGTPEYLAPEVLHKQPYDRTVDWWCLGAVLYEMLYGLPPFYSR
  NTAEMYDNILNKPLQLKPNITNSARHLLEGLLQKDRTKRLGAKDDFMEIKSHVFFSLINW
  DDLINKKITPPFNPNVSGPNDLRHFDPEFTEEPVPNSIGKSPDSVLVTASVKEAAEAFLG
  FSYAPPTDSFL
• Function: Plays an important role in cellular stress response. Contributes to regulation of renal Na(+) retention, renal K(+) elimination, salt appetite, gastric acid secretion, intestinal Na(+)/H(+) exchange and nutrient transport, insulin-dependent salt sensitivity of blood pressure, salt sensitivity of peripheral glucose uptake, cardiac repolarization and memory consolidation. Up-regulates Na(+) channels: SCNN1A/ENAC, SCN5A and ASIC1/ACCN2, K(+) channels: KCNJ1/ROMK1, KCNA1-5, KCNQ1-5 and KCNE1, epithelial Ca(2+) channels: TRPV5 and TRPV6, chloride channels: BSND, CLCN2 and CFTR, glutamate transporters: SLC1A3/EAAT1, SLC1A2 /EAAT2, SLC1A1/EAAT3, SLC1A6/EAAT4 and SLC1A7/EAAT5, amino acid transporters: SLC1A5/ASCT2, SLC38A1/SN1 and SLC6A19, creatine transporter: SLC6A8, Na(+)/dicarboxylate cotransporter: SLC13A2/NADC1, Na(+)-dependent phosphate cotransporter: SLC34A2/NAPI-2B, glutamate receptor: GRIK2/GLUR6. Up-regulates carriers: SLC9A3/NHE3, SLC12A1/NKCC2, SLC12A3/NCC, SLC5A3/SMIT, SLC2A1/GLUT1, SLC5A1/SGLT1 and SLC15A2/PEPT2. Regulates enzymes: GSK3A/B, PMM2 and Na(+)/K(+) ATPase, and transcription factors: CTNNB1 and nuclear factor NF-kappa-B. Stimulates sodium transport into epithelial cells by enhancing the stability and expression of SCNN1A/ENAC. This is achieved by phosphorylating the NEDD4L ubiquitin E3 ligase, promoting its interaction with 14-3-3 proteins, thereby preventing it from binding to SCNN1A/ENAC and targeting it for degradation. Regulates store-operated Ca(+2) entry (SOCE) by stimulating ORAI1 and STIM1. Regulates KCNJ1/ROMK1 directly via its phosphorylation or indirectly via increased interaction with SLC9A3R2/NHERF2. Phosphorylates MDM2 and activates MDM2-dependent ubiquitination of p53/TP53. Phosphorylates MAPT/TAU and mediates microtubule depolymerization and neurite formation in hippocampal neurons. Phosphorylates SLC2A4/GLUT4 and up-regulates its activity. Phosphorylates APBB1/FE65 and promotes its localization to the nucleus. Phosphorylates MAPK1/ERK2 and activates it by enhancing its interaction with MAP2K1/MEK1 and MAP2K2/MEK2. Phosphorylates FBXW7 and plays an inhibitory role in the NOTCH1 signaling. Phosphorylates FOXO1 resulting in its relocalization from the nucleus to the cytoplasm. Phosphorylates FOXO3, promoting its exit from the nucleus and interference with FOXO3-dependent transcription. Phosphorylates BRAF and MAP3K3/MEKK3 and inhibits their activity. Phosphorylates SLC9A3/NHE3 in response to dexamethasone, resulting in its activation and increased localization at the cell membrane. Phosphorylates CREB1. Necessary for vascular remodeling during angiogenesis. Sustained high levels and activity may contribute to conditions such as hypertension and diabetic nephropathy. Isoform 2 exhibited a greater effect on cell plasma membrane expression of SCNN1A/ENAC and Na(+) transport than isoform 1. Serine/threonine-protein kinase which is involved in the regulation of a wide variety of ion channels, membrane transporters, cellular enzymes, transcription factors, neuronal excitability, cell growth, proliferation, survival, migration and apoptosis.
• KEGG Pathway:
  FoxO signaling pathway (hsa04068)
  PI3K-Akt signaling pathway (hsa04151)
  Aldosterone-regulated sodium reabsorption (hsa04960)
• Reactome Pathway: Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DTT

7 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
4,5,6,7-tetrabromo-1H-benzo[d][1,2,3]triazole	DMN9YOB	Discovery agent	N.A.	Investigative	[2]
Bisindolylmaleimide-I	DMOQJZC	Discovery agent	N.A.	Investigative	[1]
CGP-57380	DMFPOUC	Discovery agent	N.A.	Investigative	[3]
CI-1040	DMF3DZX	Discovery agent	N.A.	Investigative	[1]
GSK-650394	DMNRP2L	Prostate cancer	2C82.0	Investigative	[4]
KN-62	DMLZ89P	Discovery agent	N.A.	Investigative	[1]
RO-316233	DMAGLPW	Discovery agent	N.A.	Investigative	[1]

References

• [1] Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105.
• [2] Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. J Med Chem. 2004 Dec 2;47(25):6239-47.
• [3] The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007 Dec 15;408(3):297-315.
• [4] 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. (Ligand id: 8040).