Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTOJ9QL)

• DTT Name: Endoplasmic reticulum to nucleus signaling 1 (ERN1)
• Synonyms: Serine/threonine-protein kinase/endoribonuclease IRE1; Ire1-alpha; IRE1a; IRE1; Inositol-requiring protein 1; hIRE1p; Endoplasmic reticulum-to-nucleus signaling 1
• Gene Name: ERN1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Kinase
• UniProt ID: ERN1_HUMAN
• TTD ID: T01003
• Sequence:
  MPARRLLLLLTLLLPGLGIFGSTSTVTLPETLLFVSTLDGSLHAVSKRTGSIKWTLKEDP
  VLQVPTHVEEPAFLPDPNDGSLYTLGSKNNEGLTKLPFTIPELVQASPCRSSDGILYMGK
  KQDIWYVIDLLTGEKQQTLSSAFADSLCPSTSLLYLGRTEYTITMYDTKTRELRWNATYF
  DYAASLPEDDVDYKMSHFVSNGDGLVVTVDSESGDVLWIQNYASPVVAFYVWQREGLRKV
  MHINVAVETLRYLTFMSGEVGRITKWKYPFPKETEAKSKLTPTLYVGKYSTSLYASPSMV
  HEGVAVVPRGSTLPLLEGPQTDGVTIGDKGECVITPSTDVKFDPGLKSKNKLNYLRNYWL
  LIGHHETPLSASTKMLERFPNNLPKHRENVIPADSEKKSFEEVINLVDQTSENAPTTVSR
  DVEEKPAHAPARPEAPVDSMLKDMATIILSTFLLIGWVAFIITYPLSMHQQQQLQHQQFQ
  KELEKIQLLQQQQQQLPFHPPGDTAQDGELLDTSGPYSESSGTSSPSTSPRASNHSLCSG
  SSASKAGSSPSLEQDDGDEETSVVIVGKISFCPKDVLGHGAEGTIVYRGMFDNRDVAVKR
  ILPECFSFADREVQLLRESDEHPNVIRYFCTEKDRQFQYIAIELCAATLQEYVEQKDFAH
  LGLEPITLLQQTTSGLAHLHSLNIVHRDLKPHNILISMPNAHGKIKAMISDFGLCKKLAV
  GRHSFSRRSGVPGTEGWIAPEMLSEDCKENPTYTVDIFSAGCVFYYVISEGSHPFGKSLQ
  RQANILLGACSLDCLHPEKHEDVIARELIEKMIAMDPQKRPSAKHVLKHPFFWSLEKQLQ
  FFQDVSDRIEKESLDGPIVKQLERGGRAVVKMDWRENITVPLQTDLRKFRTYKGGSVRDL
  LRAMRNKKHHYRELPAEVRETLGSLPDDFVCYFTSRFPHLLAHTYRAMELCSHERLFQPY
  YFHEPPEPQPPVTPDAL
• Function: In unstressed cells, the endoplasmic reticulum luminal domain is maintained in its inactive monomeric state by binding to the endoplasmic reticulum chaperone HSPA5/BiP. Accumulation of misfolded protein in the endoplasmic reticulum causes release of HSPA5/BiP, allowing the luminal domain to homodimerize, promoting autophosphorylation of the kinase domain and subsequent activation of the endoribonuclease activity. The endoribonuclease activity is specific for XBP1 mRNA and excises 26 nucleotides from XBP1 mRNA. The resulting spliced transcript of XBP1 encodes a transcriptional activator protein that up-regulates expression of UPR target genes. Acts as an upstream signal for ER stress-induced GORASP2-mediated unconventional (ER/Golgi-independent) trafficking of CFTR to cell membrane by modulating the expression and localization of SEC16A. Serine/threonine-protein kinase and endoribonuclease that acts as a key sensor for the endoplasmic reticulum unfolded protein response (UPR).
• KEGG Pathway:
  Autophagy - animal (hsa04140)
  Protein processing in endoplasmic reticulum (hsa04141)
  Apoptosis (hsa04210)
  Non-alcoholic fatty liver disease (hsa04932)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway: IRE1alpha activates chaperones (R-HSA-381070)

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ORIN1001	DM27RXS	Metastatic breast cancer	2C6Y	Phase 1/2	[2]

11 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
879325-11-8	DMP04Z6	N. A.	N. A.	Patented	[3]
AC1LE05K	DMPOR3G	N. A.	N. A.	Patented	[4]
BB 0223767	DM2DT6L	N. A.	N. A.	Patented	[5]
T8361	DM86BDS	N. A.	N. A.	Patented	[5]
US8614253, 29-1	DMJKFVU	N. A.	N. A.	Patented	[6]
US8614253, 29-19	DMVI83P	N. A.	N. A.	Patented	[7]
US8614253, 32-4	DMRSP2M	N. A.	N. A.	Patented	[7]
US8614253, 32-5	DMSQODK	N. A.	N. A.	Patented	[5]
US9040714, 155	DMDELNU	N. A.	N. A.	Patented	[3]
US9040714, 7	DM53Z4I	N. A.	N. A.	Patented	[3]
US9241942, 32-12	DM8GW54	N. A.	N. A.	Patented	[7]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
APY29	DMCOMLS	Solid tumour/cancer	2A00-2F9Z	Investigative	[8]
PMID24749861C34	DMJNQE1	Discovery agent	N.A.	Investigative	[1]

References

• [1] Synthesis of novel tricyclic chromenone-based inhibitors of IRE-1 RNase activity. J Med Chem. 2014 May 22;57(10):4289-301.
• [2] Clinical pipeline report, company report or official report of Orinove.
• [3] IRE-1 inhibitors. US9040714.
• [4] IRE-1 inhibitors. US9693992.
• [5] IRE-1 inhibitors. US8614253.
• [6] IRE-1 inhibitors. US9241942.
• [7] IRE-1 inhibitors. US9493435.
• [8] Quercetin ameliorates HFD-induced NAFLD by promoting hepatic VLDL assembly and lipophagy via the IRE1a/XBP1s pathway. Food Chem Toxicol. 2018 Apr;114:52-60.