Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT5OU0D)

• DTT Name: PRKR-like endoplasmic reticulum kinase (PERK)
• Synonyms: PEK
• Gene Name: EIF2AK3
• DTT Type: Patented-recorded target; [1]
• BioChemical Class: Kinase
• UniProt ID: E2AK3_HUMAN
• TTD ID: T13176
• EC Number: EC 2.7.11.1
• Sequence:
  MERAISPGLLVRALLLLLLLLGLAARTVAAGRARGLPAPTAEAAFGLGAAAAPTSATRVP
  AAGAVAAAEVTVEDAEALPAAAGEQEPRGPEPDDETELRPRGRSLVIISTLDGRIAALDP
  ENHGKKQWDLDVGSGSLVSSSLSKPEVFGNKMIIPSLDGALFQWDQDRESMETVPFTVES
  LLESSYKFGDDVVLVGGKSLTTYGLSAYSGKVRYICSALGCRQWDSDEMEQEEDILLLQR
  TQKTVRAVGPRSGNEKWNFSVGHFELRYIPDMETRAGFIESTFKPNENTEESKIISDVEE
  QEAAIMDIVIKVSVADWKVMAFSKKGGHLEWEYQFCTPIASAWLLKDGKVIPISLFDDTS
  YTSNDDVLEDEEDIVEAARGATENSVYLGMYRGQLYLQSSVRISEKFPSSPKALESVTNE
  NAIIPLPTIKWKPLIHSPSRTPVLVGSDEFDKCLSNDKFSHEEYSNGALSILQYPYDNGY
  YLPYYKRERNKRSTQITVRFLDNPHYNKNIRKKDPVLLLHWWKEIVATILFCIIATTFIV
  RRLFHPHPHRQRKESETQCQTENKYDSVSGEANDSSWNDIKNSGYISRYLTDFEPIQCLG
  RGGFGVVFEAKNKVDDCNYAIKRIRLPNRELAREKVMREVKALAKLEHPGIVRYFNAWLE
  APPEKWQEKMDEIWLKDESTDWPLSSPSPMDAPSVKIRRMDPFATKEHIEIIAPSPQRSR
  SFSVGISCDQTSSSESQFSPLEFSGMDHEDISESVDAAYNLQDSCLTDCDVEDGTMDGND
  EGHSFELCPSEASPYVRSRERTSSSIVFEDSGCDNASSKEEPKTNRLHIGNHCANKLTAF
  KPTSSKSSSEATLSISPPRPTTLSLDLTKNTTEKLQPSSPKVYLYIQMQLCRKENLKDWM
  NGRCTIEERERSVCLHIFLQIAEAVEFLHSKGLMHRDLKPSNIFFTMDDVVKVGDFGLVT
  AMDQDEEEQTVLTPMPAYARHTGQVGTKLYMSPEQIHGNSYSHKVDIFSLGLILFELLYP
  FSTQMERVRTLTDVRNLKFPPLFTQKYPCEYVMVQDMLSPSPMERPEAINIIENAVFEDL
  DFPGKTVLRQRSRSLSSSGTKHSRQSNNSHSPLPSN
• Function: Converts phosphorylated eIF-2-alpha/EIF2S1 either in a global protein synthesis inhibitor, leading to a reduced overall utilization of amino acids, or to a translation initiation activator of specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming of amino acid biosynthetic gene expression to alleviate nutrient depletion. Serves as a critical effector of unfolded protein response (UPR)-induced G1 growth arrest due to the loss of cyclin-D1 (CCND1). Involved in control of mitochondrial morphology and function. Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2-alpha/EIF2S1) on 'Ser-52' during the unfolded protein response (UPR) and in response to low amino acid availability.
• KEGG Pathway:
  Mitophagy - animal (hsa04137)
  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)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Hepatitis C (hsa05160)
  Measles (hsa05162)
  Herpes simplex virus 1 infection (hsa05168)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  ALK mutants bind TKIs (R-HSA-9700645)
  Signaling by ALK fusions and activated point mutants (R-HSA-9725370)
  PERK regulates gene expression (R-HSA-381042)

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
HC-5404	DMKFZW5	Breast cancer	2C60-2C65	Phase 1	[2]

17 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Indoline derivative 10	DMTPGRO	N. A.	N. A.	Patented	[1]
Indoline derivative 11	DM6JR3X	N. A.	N. A.	Patented	[1]
Indoline derivative 2	DMASXR5	N. A.	N. A.	Patented	[1]
Indoline derivative 3	DM20YBJ	N. A.	N. A.	Patented	[1]
Indoline derivative 6	DMU5KWC	N. A.	N. A.	Patented	[1]
Indoline derivative 7	DMXS46Y	N. A.	N. A.	Patented	[1]
Indoline derivative 8	DMS8KMB	N. A.	N. A.	Patented	[1]
Indoline derivative 9	DMCORT3	N. A.	N. A.	Patented	[1]
Phenylpyrrolidinone derivative 1	DMPAI5C	N. A.	N. A.	Patented	[1]
Phenylpyrrolidinone derivative 2	DMF3NCO	N. A.	N. A.	Patented	[1]
Phenylpyrrolidinone derivative 3	DMPZKQN	N. A.	N. A.	Patented	[1]
Phenylpyrrolidinone derivative 4	DMSX47Q	N. A.	N. A.	Patented	[1]
Phenylpyrrolidinone derivative 5	DMZSTLH	N. A.	N. A.	Patented	[1]
Tricyclic isoxazoloquinazoline derivative 1	DM6QSND	N. A.	N. A.	Patented	[1]
Tricyclic isoxazoloquinazoline derivative 2	DMH4TY1	N. A.	N. A.	Patented	[1]
Tricyclic isoxazoloquinazoline derivative 3	DML2PWF	N. A.	N. A.	Patented	[1]
Tricyclic isoxazoloquinazoline derivative 4	DM8VIM4	N. A.	N. A.	Patented	[1]

1 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GSK2606414	DMLASOF	Discovery agent	N.A.	Investigative	[3]

References

• [1] Protein kinase R(PKR)-like endoplasmic reticulum kinase (PERK) inhibitors: a patent review (2010-2015).Expert Opin Ther Pat. 2017 Jan;27(1):37-48.
• [2] Clinical pipeline report, company report or official report of HiberCell
• [3] Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). J Med Chem. 2012 Aug 23;55(16):7193-207.