Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4JHN4Y)

• DOT Name: Proline-rich AKT1 substrate 1 (AKT1S1)
• Synonyms: 40 kDa proline-rich AKT substrate
• Gene Name: AKT1S1
• Related Disease:
  Cerebral infarction
  Gallbladder cancer
  Gallbladder carcinoma
  Glioma
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Esophageal squamous cell carcinoma
  Ewing sarcoma
  Hamartoma
  Hepatocellular carcinoma
  Hyperinsulinemia
  Kidney cancer
  Kidney neoplasm
  Lung cancer
  Lung carcinoma
  Myocardial infarction
  Neoplasm
  Non-small-cell lung cancer
  Prion disease
  Prostate cancer
  Prostate carcinoma
  Renal carcinoma
  Renal cell carcinoma
  Adult glioblastoma
  Cutaneous melanoma
  Glioblastoma multiforme
  Lung adenocarcinoma
  Melanoma
  Retinopathy
• UniProt ID: AKTS1_HUMAN
• PDB ID: 5WBL; 5WBU; 5WBY; 6SB0
• Pfam ID: PF15798
• Sequence:
  MASGRPEELWEAVVGAAERFRARTGTELVLLTAAPPPPPRPGPCAYAAHGRGALAEAARR
  CLHDIALAHRAATAARPPAPPPAPQPPSPTPSPPRPTLAREDNEEDEDEPTETETSGEQL
  GISDNGGLFVMDEDATLQDLPPFCESDPESTDDGSLSEETPAGPPTCSVPPASALPTQQY
  AKSLPVSVPVWGFKEKRTEARSSDEENGPPSSPDLDRIAASMRALVLREAEDTQVFGDLP
  RPRLNTSDFQKLKRKY
• Function: Negative regulator of the mechanistic target of rapamycin complex 1 (mTORC1), an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation and growth. In absence of insulin and nutrients, AKT1S1 associates with the mTORC1 complex and directly inhibits mTORC1 activity by blocking the MTOR substrate-recruitment site. In response to insulin and nutrients, AKT1S1 dissociates from mTORC1. Its activity is dependent on its phosphorylation state and binding to 14-3-3. May also play a role in nerve growth factor-mediated neuroprotection.
• Tissue Specificity: Widely expressed with highest levels of expression in liver and heart. Expressed at higher levels in cancer cell lines (e.g. A-549 and HeLa) than in normal cell lines (e.g. HEK293).
• KEGG Pathway:
  Autophagy - animal (hsa04140)
  mTOR sig.ling pathway (hsa04150)
  AMPK sig.ling pathway (hsa04152)
  Longevity regulating pathway (hsa04211)
  Longevity regulating pathway - multiple species (hsa04213)
  Thermogenesis (hsa04714)
  Shigellosis (hsa05131)
• Reactome Pathway:
  mTORC1-mediated signalling (R-HSA-166208)
  AKT phosphorylates targets in the cytosol (R-HSA-198323)
  HSF1-dependent transactivation (R-HSA-3371571)
  Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-5674400)
  MTOR signalling (R-HSA-165159)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebral infarction	DISR1WNP	Definitive	Biomarker	[1]
Gallbladder cancer	DISXJUAF	Definitive	Biomarker	[2]
Gallbladder carcinoma	DISD6ACL	Definitive	Biomarker	[2]
Glioma	DIS5RPEH	Definitive	Posttranslational Modification	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[5]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Posttranslational Modification	[6]
Breast carcinoma	DIS2UE88	Strong	Posttranslational Modification	[6]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[7]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[8]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[9]
Hamartoma	DIS0I87H	Strong	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[11]
Hyperinsulinemia	DISIDWT6	Strong	Altered Expression	[12]
Kidney cancer	DISBIPKM	Strong	Altered Expression	[13]
Kidney neoplasm	DISBNZTN	Strong	Altered Expression	[13]
Lung cancer	DISCM4YA	Strong	Biomarker	[14]
Lung carcinoma	DISTR26C	Strong	Biomarker	[14]
Myocardial infarction	DIS655KI	Strong	Biomarker	[15]
Neoplasm	DISZKGEW	Strong	Biomarker	[16]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[17]
Prion disease	DISOUMB0	Strong	Biomarker	[18]
Prostate cancer	DISF190Y	Strong	Biomarker	[19]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[19]
Renal carcinoma	DISER9XT	Strong	Altered Expression	[13]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[7]
Adult glioblastoma	DISVP4LU	Limited	Posttranslational Modification	[20]
Cutaneous melanoma	DIS3MMH9	Limited	Altered Expression	[4]
Glioblastoma multiforme	DISK8246	Limited	Posttranslational Modification	[20]
Lung adenocarcinoma	DISD51WR	Limited	Altered Expression	[4]
Melanoma	DIS1RRCY	Limited	Biomarker	[21]
Retinopathy	DISB4B0F	Limited	Posttranslational Modification	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Proline-rich AKT1 substrate 1 (AKT1S1).	[23]
Estradiol	DMUNTE3	Approved	Estradiol increases the phosphorylation of Proline-rich AKT1 substrate 1 (AKT1S1).	[26]
AZD5363	DM9SKW8	Approved	AZD5363 decreases the phosphorylation of Proline-rich AKT1 substrate 1 (AKT1S1).	[29]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the phosphorylation of Proline-rich AKT1 substrate 1 (AKT1S1).	[32]
Rigosertib	DMOSTXF	Phase 3	Rigosertib decreases the phosphorylation of Proline-rich AKT1 substrate 1 (AKT1S1).	[33]
AZD4547	DM3827C	Phase 2/3	AZD4547 decreases the phosphorylation of Proline-rich AKT1 substrate 1 (AKT1S1).	[29]
GDC0941	DM1YAK6	Phase 2	GDC0941 decreases the phosphorylation of Proline-rich AKT1 substrate 1 (AKT1S1).	[34]
MK-2206	DMT1OZ6	Phase 2	MK-2206 decreases the phosphorylation of Proline-rich AKT1 substrate 1 (AKT1S1).	[35]
PF-04691502	DMS610L	Phase 2	PF-04691502 decreases the phosphorylation of Proline-rich AKT1 substrate 1 (AKT1S1).	[36]
GSK2141795	DMSHE70	Phase 2	GSK2141795 decreases the phosphorylation of Proline-rich AKT1 substrate 1 (AKT1S1).	[37]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Proline-rich AKT1 substrate 1 (AKT1S1).	[38]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the phosphorylation of Proline-rich AKT1 substrate 1 (AKT1S1).	[40]
AZD8186	DMWYF1H	Phase 1	AZD8186 affects the phosphorylation of Proline-rich AKT1 substrate 1 (AKT1S1).	[29]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Proline-rich AKT1 substrate 1 (AKT1S1).	[42]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Proline-rich AKT1 substrate 1 (AKT1S1).	[42]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Proline-rich AKT1 substrate 1 (AKT1S1).	[45]
Icariside II	DM3DB8X	Investigative	Icariside II decreases the phosphorylation of Proline-rich AKT1 substrate 1 (AKT1S1).	[46]
STO609	DMZSOG2	Investigative	STO609 decreases the phosphorylation of Proline-rich AKT1 substrate 1 (AKT1S1).	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Proline-rich AKT1 substrate 1 (AKT1S1).	[24]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Proline-rich AKT1 substrate 1 (AKT1S1).	[25]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Proline-rich AKT1 substrate 1 (AKT1S1).	[27]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Proline-rich AKT1 substrate 1 (AKT1S1).	[28]
Cabazitaxel	DMPAZHC	Approved	Cabazitaxel decreases the expression of Proline-rich AKT1 substrate 1 (AKT1S1).	[30]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Proline-rich AKT1 substrate 1 (AKT1S1).	[31]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Proline-rich AKT1 substrate 1 (AKT1S1).	[39]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Proline-rich AKT1 substrate 1 (AKT1S1).	[41]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Proline-rich AKT1 substrate 1 (AKT1S1).	[43]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Proline-rich AKT1 substrate 1 (AKT1S1).	[44]

References

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