Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ6QO99)

• DOT Name: Serine/threonine-protein kinase Sgk3 (SGK3)
• Synonyms: EC 2.7.11.1; Cytokine-independent survival kinase; Serum/glucocorticoid-regulated kinase 3; Serum/glucocorticoid-regulated kinase-like
• Gene Name: SGK3
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Alzheimer disease
  Autosomal dominant hypophosphatemic rickets
  Breast cancer
  Colon cancer
  Colon carcinoma
  Estrogen-receptor positive breast cancer
  Hepatocellular carcinoma
  Influenza
  leukaemia
  Leukemia
  Neoplasm
  Neuralgia
  Plasma cell myeloma
  Polycystic ovarian syndrome
  Vitamin D-dependent rickets, type 2
  Alopecia
  Clear cell renal carcinoma
  Renal cell carcinoma
  Melanoma
  Bone osteosarcoma
  Breast carcinoma
  Hypophosphatemic rickets
  Osteosarcoma
  Prostate cancer
  Prostate carcinoma
• UniProt ID: SGK3_HUMAN
• PDB ID: 6EDX
• EC Number: 2.7.11.1
• Pfam ID: PF00069 ; PF00433 ; PF00787
• Sequence:
  MQRDHTMDYKESCPSVSIPSSDEHREKKKRFTVYKVLVSVGRSEWFVFRRYAEFDKLYNT
  LKKQFPAMALKIPAKRIFGDNFDPDFIKQRRAGLNEFIQNLVRYPELYNHPDVRAFLQMD
  SPKHQSDPSEDEDERSSQKLHSTSQNINLGPSGNPHAKPTDFDFLKVIGKGSFGKVLLAK
  RKLDGKFYAVKVLQKKIVLNRKEQKHIMAERNVLLKNVKHPFLVGLHYSFQTTEKLYFVL
  DFVNGGELFFHLQRERSFPEHRARFYAAEIASALGYLHSIKIVYRDLKPENILLDSVGHV
  VLTDFGLCKEGIAISDTTTTFCGTPEYLAPEVIRKQPYDNTVDWWCLGAVLYEMLYGLPP
  FYCRDVAEMYDNILHKPLSLRPGVSLTAWSILEELLEKDRQNRLGAKEDFLEIQNHPFFE
  SLSWADLVQKKIPPPFNPNVAGPDDIRNFDTAFTEETVPYSVCVSSDYSIVNASVLEADD
  AFVGFSYAPPSEDLFL
• Function: Serine/threonine-protein kinase which is involved in the regulation of a wide variety of ion channels, membrane transporters, cell growth, proliferation, survival and migration. Up-regulates Na(+) channels: SCNN1A/ENAC and SCN5A, K(+) channels: KCNA3/KV1.3, KCNE1, KCNQ1 and KCNH2/HERG, epithelial Ca(2+) channels: TRPV5 and TRPV6, chloride channel: BSND, creatine transporter: SLC6A8, Na(+)/dicarboxylate cotransporter: SLC13A2/NADC1, Na(+)-dependent phosphate cotransporter: SLC34A2/NAPI-2B, amino acid transporters: SLC1A5/ASCT2 and SLC6A19, glutamate transporters: SLC1A3/EAAT1, SLC1A6/EAAT4 and SLC1A7/EAAT5, glutamate receptors: GRIA1/GLUR1 and GRIK2/GLUR6, Na(+)/H(+) exchanger: SLC9A3/NHE3, and the Na(+)/K(+) ATPase. Plays a role in the regulation of renal tubular phosphate transport and bone density. Phosphorylates NEDD4L and GSK3B. Positively regulates ER transcription activity through phosphorylation of FLII. Negatively regulates the function of ITCH/AIP4 via its phosphorylation and thereby prevents CXCR4 from being efficiently sorted to lysosomes.
• Tissue Specificity: Expressed in most tissues with highest levels in pancreas, kidney liver, heart and brain and lower levels in lung, placenta and skeletal muscle. Expression is higher in ER-positive breast tumors than ER-negative breast tumors.
• KEGG Pathway:
  FoxO sig.ling pathway (hsa04068)
  PI3K-Akt sig.ling pathway (hsa04151)
• Reactome Pathway: Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Autosomal dominant hypophosphatemic rickets	DISG799S	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[7]
Influenza	DIS3PNU3	Strong	Biomarker	[8]
leukaemia	DISS7D1V	Strong	Biomarker	[1]
Leukemia	DISNAKFL	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[7]
Neuralgia	DISWO58J	Strong	Biomarker	[9]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[10]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Altered Expression	[11]
Vitamin D-dependent rickets, type 2	DISZHFC3	Strong	Genetic Variation	[4]
Alopecia	DIS37HU4	moderate	Biomarker	[12]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[13]
Renal cell carcinoma	DISQZ2X8	moderate	Biomarker	[13]
Melanoma	DIS1RRCY	Disputed	Biomarker	[14]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[15]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[2]
Hypophosphatemic rickets	DIS7XTW5	Limited	Autosomal dominant	[16]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[15]
Prostate cancer	DISF190Y	Limited	Biomarker	[17]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[17]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	Serine/threonine-protein kinase Sgk3 (SGK3) decreases the response to substance of Afimoxifene.	[38]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Serine/threonine-protein kinase Sgk3 (SGK3).	[18]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Serine/threonine-protein kinase Sgk3 (SGK3).	[23]
GDC0941	DM1YAK6	Phase 2	GDC0941 decreases the phosphorylation of Serine/threonine-protein kinase Sgk3 (SGK3).	[32]

26 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[21]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[22]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[24]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[25]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[26]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[27]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[25]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[22]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[22]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[28]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[29]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[30]
Estrone	DM5T6US	Approved	Estrone increases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[22]
Mestranol	DMG3F94	Approved	Mestranol increases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[22]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[31]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[25]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[22]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[33]
HEXESTROL	DM9AGWQ	Withdrawn from market	HEXESTROL increases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[34]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[35]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[36]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Serine/threonine-protein kinase Sgk3 (SGK3).	[37]

References

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• [4] Mutation of SGK3, a Novel Regulator of Renal Phosphate Transport, Causes Autosomal Dominant Hypophosphatemic Rickets.J Clin Endocrinol Metab. 2020 Jun 1;105(6):dgz260. doi: 10.1210/clinem/dgz260.
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• [34] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
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