Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Rotamase Pin1 (PIN1)
• Synonyms: Prolyl isomerase Pin1; Peptidyl-prolyl cis-trans isomerase Pin1; Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1; Peptidyl prolyl cis/trans isomerase Pin1; PPIase Pin1
• Gene Name: PIN1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Cis-trans-isomerase
• UniProt ID: PIN1_HUMAN
• TTD ID: T16308
• EC Number: EC 5.2.1.8
• Sequence:
  MADEEKLPPGWEKRMSRSSGRVYYFNHITNASQWERPSGNSSSGGKNGQGEPARVRCSHL
  LVKHSQSRRPSSWRQEKITRTKEEALELINGYIQKIKSGEEDFESLASQFSDCSSAKARG
  DLGAFSRGQMQKPFEDASFALRTGEMSGPVFTDSGIHIILRTE
• Function: By inducing conformational changes in a subset of phosphorylated proteins, acts as a molecular switch in multiple cellular processes (, Ref. 21). Displays a preference for acidic residues located N-terminally to the proline bond to be isomerized. Regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity. Down-regulates kinase activity of BTK. Can transactivate multiple oncogenes and induce centrosome amplification, chromosome instability and cell transformation. Required for the efficient dephosphorylation and recycling of RAF1 after mitogen activation. Binds and targets PML and BCL6 for degradation in a phosphorylation-dependent manner. Acts as a regulator of JNK cascade by binding to phosphorylated FBXW7, disrupting FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation: degradation of FBXW7 leads to subsequent stabilization of JUN. May facilitate the ubiquitination and proteasomal degradation of RBBP8/CtIP through CUL3/KLHL15 E3 ubiquitin-protein ligase complex, hence favors DNA double-strand repair through error-prone non-homologous end joining (NHEJ) over error-free, RBBP8-mediated homologous recombination (HR). Peptidyl-prolyl cis/trans isomerase (PPIase) that binds to and isomerizes specific phosphorylated Ser/Thr-Pro (pSer/Thr-Pro) motifs.
• KEGG Pathway: RIG-I-like receptor signaling pathway (hsa04622)
• Reactome Pathway:
  Negative regulators of RIG-I/MDA5 signaling (R-HSA-936440)
  ISG15 antiviral mechanism (R-HSA-1169408)

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
Avastin+/-Tarceva	DMA86FL	Non-small-cell lung cancer	2C25.Y	Phase 3	[1]

10 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(R)-2-(2-naphthamido)-3-m-tolylpropanoic acid	DMVEMNA	Discovery agent	N.A.	Investigative	[2]
(R)-2-(2-naphthamido)-3-p-tolylpropanoic acid	DMXGCYZ	Discovery agent	N.A.	Investigative	[2]
(R)-2-(2-naphthamido)-5-phenylpent-4-ynoic acid	DM9WL6O	Discovery agent	N.A.	Investigative	[2]
(R)-3-(2-naphthamido)-4-m-tolylbutanoic acid	DM5TH2W	Discovery agent	N.A.	Investigative	[2]
(R,)-2-(2-naphthamido)-5-phenylpent-4-enoic acid	DMCW5A9	Discovery agent	N.A.	Investigative	[2]
3,6,9,12,15,18-HEXAOXAICOSANE	DMY26JI	Discovery agent	N.A.	Investigative	[3]
Ac-Bth-Thr(PO3H2)-Pip-Nal-Gln-NH2	DMSE29N	Discovery agent	N.A.	Investigative	[4]
Ac-Phe-D-Thr(PO3H2)-Pip-Nal-Gln-NH2	DM6ONY7	Discovery agent	N.A.	Investigative	[4]
Ac-Phe-Thr(PO3H2)-Pip-Nal-Gln-NH2	DMSWTPX	Discovery agent	N.A.	Investigative	[4]
Beta-(2-Naphthyl)-Alanine	DMP21ZO	Discovery agent	N.A.	Investigative	[3]

References

• [1] Overexpression of PIN1 Enhances Cancer Growth and Aggressiveness with Cyclin D1 Induction in EBV-Associated Nasopharyngeal Carcinoma.PLoS One. 2016 Jun 3;11(6):e0156833.
• [2] Structure-based design of novel human Pin1 inhibitors (II). Bioorg Med Chem Lett. 2010 Apr 1;20(7):2210-4.
• [3] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [4] Nanomolar inhibitors of the peptidyl prolyl cis/trans isomerase Pin1 from combinatorial peptide libraries. J Med Chem. 2006 Apr 6;49(7):2147-50.