Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTEAD9J)

• DTT Name: Proteasome beta-8 (PS beta-8)
• Synonyms: Y2; Really interesting new gene 10 protein; RING10; Proteasome subunit beta-5i; Proteasome subunit beta type-8; Proteasome component C13; PSMB5i; Multicatalytic endopeptidase complex subunit C13; Macropain subunit C13; Low molecular mass protein 7; LMP7
• Gene Name: PSMB8
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Peptidase
• UniProt ID: PSB8_HUMAN
• TTD ID: T77350
• EC Number: EC 3.4.25.1
• Sequence:
  MALLDVCGAPRGQRPESALPVAGSGRRSDPGHYSFSMRSPELALPRGMQPTEFFQSLGGD
  GERNVQIEMAHGTTTLAFKFQHGVIAAVDSRASAGSYISALRVNKVIEINPYLLGTMSGC
  AADCQYWERLLAKECRLYYLRNGERISVSAASKLLSNMMCQYRGMGLSMGSMICGWDKKG
  PGLYYVDEHGTRLSGNMFSTGSGNTYAYGVMDSGYRPNLSPEEAYDLGRRAIAYATHRDS
  YSGGVVNMYHMKEDGWVKVESTDVSDLLHQYREANQ
• Function: The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Replacement of PSMB5 by PSMB8 increases the capacity of the immunoproteasome to cleave model peptides after hydrophobic and basic residues. Acts as a major component of interferon gamma-induced sensitivity. Plays a key role in apoptosis via the degradation of the apoptotic inhibitor MCL1. May be involved in the inflammatory response pathway. In cancer cells, substitution of isoform 1 (E2) by isoform 2 (E1) results in immunoproteasome deficiency. Required for the differentiation of preadipocytes into adipocytes. The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH.
• KEGG Pathway: Proteasome (hsa03050)
• Reactome Pathway:
  Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha (R-HSA-1234176)
  ER-Phagosome pathway (R-HSA-1236974)
  Cross-presentation of soluble exogenous antigens (endosomes) (R-HSA-1236978)
  Autodegradation of Cdh1 by Cdh1 (R-HSA-174084)
  SCF-beta-TrCP mediated degradation of Emi1 (R-HSA-174113)
  APC/C (R-HSA-174154)
  APC/C (R-HSA-174178)
  Cdc20 (R-HSA-174184)
  Vpu mediated degradation of CD4 (R-HSA-180534)
  Vif-mediated degradation of APOBEC3G (R-HSA-180585)
  SCF(Skp2)-mediated degradation of p27/p21 (R-HSA-187577)
  Degradation of beta-catenin by the destruction complex (R-HSA-195253)
  Downstream TCR signaling (R-HSA-202424)
  Regulation of activated PAK-2p34 by proteasome mediated degradation (R-HSA-211733)
  Separation of Sister Chromatids (R-HSA-2467813)
  FCERI mediated NF-kB activation (R-HSA-2871837)
  Autodegradation of the E3 ubiquitin ligase COP1 (R-HSA-349425)
  Regulation of ornithine decarboxylase (ODC) (R-HSA-350562)
  ABC-family proteins mediated transport (R-HSA-382556)
  AUF1 (hnRNP D0) binds and destabilizes mRNA (R-HSA-450408)
  Asymmetric localization of PCP proteins (R-HSA-4608870)
  Degradation of AXIN (R-HSA-4641257)
  Degradation of DVL (R-HSA-4641258)
  Hedgehog ligand biogenesis (R-HSA-5358346)
  Hh mutants are degraded by ERAD (R-HSA-5362768)
  Dectin-1 mediated noncanonical NF-kB signaling (R-HSA-5607761)
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  Degradation of GLI1 by the proteasome (R-HSA-5610780)
  Degradation of GLI2 by the proteasome (R-HSA-5610783)
  GLI3 is processed to GLI3R by the proteasome (R-HSA-5610785)
  Hedgehog 'on' state (R-HSA-5632684)
  Regulation of RAS by GAPs (R-HSA-5658442)
  TNFR2 non-canonical NF-kB pathway (R-HSA-5668541)
  NIK-->noncanonical NF-kB signaling (R-HSA-5676590)
  Defective CFTR causes cystic fibrosis (R-HSA-5678895)
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  UCH proteinases (R-HSA-5689603)
  Ub-specific processing proteases (R-HSA-5689880)
  Assembly of the pre-replicative complex (R-HSA-68867)
  Orc1 removal from chromatin (R-HSA-68949)
  CDK-mediated phosphorylation and removal of Cdc6 (R-HSA-69017)
  G2/M Checkpoints (R-HSA-69481)
  Ubiquitin Mediated Degradation of Phosphorylated Cdc25A (R-HSA-69601)
  Ubiquitin-dependent degradation of Cyclin D (R-HSA-75815)
  The role of GTSE1 in G2/M progression after G2 checkpoint (R-HSA-8852276)
  FBXL7 down-regulates AURKA during mitotic entry and in early mitosis (R-HSA-8854050)
  RUNX1 regulates transcription of genes involved in differentiation of HSCs (R-HSA-8939236)
  Regulation of RUNX2 expression and activity (R-HSA-8939902)
  Regulation of RUNX3 expression and activity (R-HSA-8941858)
  Regulation of PTEN stability and activity (R-HSA-8948751)
  Neddylation (R-HSA-8951664)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Interleukin-1 signaling (R-HSA-9020702)
  Interferon alpha/beta signaling (R-HSA-909733)
  Negative regulation of NOTCH4 signaling (R-HSA-9604323)
  KEAP1-NFE2L2 pathway (R-HSA-9755511)
  GSK3B and BTRC (R-HSA-9762114)
  Antigen processing (R-HSA-983168)
  Activation of NF-kappaB in B cells (R-HSA-1169091)

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
M3258	DM6PI5B	Multiple myeloma	2A83	Phase 1	[2]

30 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Dipeptide analog 1	DM2OTJS	N. A.	N. A.	Patented	[1]
Peptide analog 11	DML9C64	N. A.	N. A.	Patented	[1]
Peptide analog 13	DMWI6V3	N. A.	N. A.	Patented	[1]
Peptide analog 17	DMJ91EM	N. A.	N. A.	Patented	[1]
Peptide analog 19	DMLIVT6	N. A.	N. A.	Patented	[1]
Peptide analog 21	DMJDFS1	N. A.	N. A.	Patented	[1]
Peptide analog 23	DMDU21R	N. A.	N. A.	Patented	[1]
Peptide analog 25	DMFBQHZ	N. A.	N. A.	Patented	[1]
Peptide analog 27	DML4XJ2	N. A.	N. A.	Patented	[1]
Peptide analog 28	DMHT4PF	N. A.	N. A.	Patented	[1]
Peptide analog 31	DMS9O6I	N. A.	N. A.	Patented	[1]
Peptide analog 33	DML5P6O	N. A.	N. A.	Patented	[1]
Peptide analog 34	DMG4EOP	N. A.	N. A.	Patented	[1]
Peptide analog 41	DM96KXE	N. A.	N. A.	Patented	[1]
PMID29865878-Compound-43	DMQUE6D	N. A.	N. A.	Patented	[1]
PMID29865878-Compound-44	DMRTQ4I	N. A.	N. A.	Patented	[1]
PMID29865878-Compound-46	DMP3MXK	N. A.	N. A.	Patented	[1]
PMID29865878-Compound-48	DMVQTR2	N. A.	N. A.	Patented	[1]
PMID29865878-Compound-49	DMK0GTV	N. A.	N. A.	Patented	[1]
PMID29865878-Compound-51	DM0LXT2	N. A.	N. A.	Patented	[1]
PMID29865878-Compound-53	DM6JV1W	N. A.	N. A.	Patented	[1]
PMID29865878-Compound-55	DMY52ZB	N. A.	N. A.	Patented	[1]
PMID29865878-Compound-57	DM3VQ1Y	N. A.	N. A.	Patented	[1]
PMID29865878-Compound-58	DMO108N	N. A.	N. A.	Patented	[1]
PMID29865878-Compound-59	DMM73VG	N. A.	N. A.	Patented	[1]
PMID29865878-Compound-61	DMG7VF1	N. A.	N. A.	Patented	[1]
PMID29865878-Compound-62	DML47KS	N. A.	N. A.	Patented	[1]
PMID29865878-Compound-63	DMEM2I8	N. A.	N. A.	Patented	[1]
PMID29865878-Compound-64	DM1U6H2	N. A.	N. A.	Patented	[1]
PMID29865878-Compound-8	DMX1E6O	N. A.	N. A.	Patented	[1]

1 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
HT1042	DMZRPM5	Discovery agent	N.A.	Investigative	[3]

References

• [1] A patent review of immunoproteasome inhibitors.Expert Opin Ther Pat. 2018 Jul;28(7):517-540.
• [2] Clinical pipeline report, company report or official report of EMD Serono.
• [3] 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. (Target id: 2408).