Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5BPAZ4)

• DOT Name: S-phase kinase-associated protein 1 (SKP1)
• Synonyms: Cyclin-A/CDK2-associated protein p19; p19A; Organ of Corti protein 2; OCP-2; Organ of Corti protein II; OCP-II; RNA polymerase II elongation factor-like protein; SIII; Transcription elongation factor B polypeptide 1-like; p19skp1
• Gene Name: SKP1
• Related Disease:
  Asthma
  Brugada syndrome
  Deafness
  Endometrial carcinoma
  Late-onset Parkinson disease
  Lung adenocarcinoma
  Parkinson disease
  Schizophrenia
  Skin cancer
  Ventricular tachycardia
  Plasma cell myeloma
  Advanced cancer
  Cutaneous mastocytosis
  facioscapulohumeral muscular dystrophy
  Huntington disease
  Lung cancer
  Lung carcinoma
  Neoplasm
  Neuroblastoma
  Spinocerebellar ataxia type 3
  Squamous cell carcinoma
  Toxoplasmosis
• UniProt ID: SKP1_HUMAN
• PDB ID: 1FQV ; 1FS1 ; 1FS2 ; 1LDK ; 1P22 ; 2ASS ; 2AST ; 2E31 ; 2E32 ; 2OVP ; 2OVQ ; 2OVR ; 3L2O ; 3WSO ; 4I6J ; 5IBK ; 5JH5 ; 5K35 ; 5V4B ; 5VZT ; 5VZU ; 5XYL ; 6BVA ; 6BYH ; 6C16 ; 6M90 ; 6M91 ; 6M92 ; 6M93 ; 6M94 ; 6O60 ; 6TTU ; 6VCD ; 6W66 ; 6WCQ ; 6WNX ; 7B5L ; 7B5M ; 7B5R ; 7T1Y ; 7T1Z ; 7Z8B ; 7Z8T ; 7Z8V ; 7ZBW ; 7ZBZ ; 8BYA ; 8BYL ; 8CDJ ; 8CDK ; 8OR0 ; 8OR3 ; 8OR4
• Pfam ID: PF01466 ; PF03931
• Sequence:
  MPSIKLQSSDGEIFEVDVEIAKQSVTIKTMLEDLGMDDEGDDDPVPLPNVNAAILKKVIQ
  WCTHHKDDPPPPEDDENKEKRTDDIPVWDQEFLKVDQGTLFELILAANYLDIKGLLDVTC
  KTVANMIKGKTPEEIRKTFNIKNDFTEEEEAQVRKENQWCEEK
• Function: Essential component of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex, which mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. In the SCF complex, serves as an adapter that links the F-box protein to CUL1. The functional specificity of the SCF complex depends on the F-box protein as substrate recognition component. SCF(BTRC) and SCF(FBXW11) direct ubiquitination of CTNNB1 and participate in Wnt signaling. SCF(FBXW11) directs ubiquitination of phosphorylated NFKBIA. SCF(BTRC) directs ubiquitination of NFKBIB, NFKBIE, ATF4, SMAD3, SMAD4, CDC25A, FBXO5, CEP68 and probably NFKB2. SCF(SKP2) directs ubiquitination of phosphorylated CDKN1B/p27kip and is involved in regulation of G1/S transition. SCF(SKP2) directs ubiquitination of ORC1, CDT1, RBL2, ELF4, CDKN1A, RAG2, FOXO1A, and probably MYC and TAL1. SCF(FBXW7) directs ubiquitination of cyclin E, NOTCH1 released notch intracellular domain (NICD), and probably PSEN1. SCF(FBXW2) directs ubiquitination of GCM1. SCF(FBXO32) directs ubiquitination of MYOD1. SCF(FBXO7) directs ubiquitination of BIRC2 and DLGAP5. SCF(FBXO33) directs ubiquitination of YBX1. SCF(FBXO11) directs ubiquitination of BCL6 and DTL but does not seem to direct ubiquitination of TP53. SCF(BTRC) mediates the ubiquitination of NFKBIA at 'Lys-21' and 'Lys-22'; the degradation frees the associated NFKB1-RELA dimer to translocate into the nucleus and to activate transcription. SCF(CCNF) directs ubiquitination of CCP110. SCF(FBXL3) and SCF(FBXL21) direct ubiquitination of CRY1 and CRY2. SCF(FBXO9) directs ubiquitination of TTI1 and TELO2. SCF(FBXO10) directs ubiquitination of BCL2.
• KEGG Pathway:
  Polycomb repressive complex (hsa03083)
  Cell cycle (hsa04110)
  Oocyte meiosis (hsa04114)
  Ubiquitin mediated proteolysis (hsa04120)
  Protein processing in endoplasmic reticulum (hsa04141)
  Wnt sig.ling pathway (hsa04310)
  TGF-beta sig.ling pathway (hsa04350)
  Circadian rhythm (hsa04710)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Human immunodeficiency virus 1 infection (hsa05170)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  Prolactin receptor signaling (R-HSA-1170546)
  SCF-beta-TrCP mediated degradation of Emi1 (R-HSA-174113)
  Vpu mediated degradation of CD4 (R-HSA-180534)
  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)
  NOTCH1 Intracellular Domain Regulates Transcription (R-HSA-2122947)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling (R-HSA-2644607)
  FCERI mediated NF-kB activation (R-HSA-2871837)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  Circadian Clock (R-HSA-400253)
  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)
  NIK-->noncanonical NF-kB signaling (R-HSA-5676590)
  MAP3K8 (TPL2)-dependent MAPK1/3 activation (R-HSA-5684264)
  Orc1 removal from chromatin (R-HSA-68949)
  Cyclin D associated events in G1 (R-HSA-69231)
  FBXL7 down-regulates AURKA during mitotic entry and in early mitosis (R-HSA-8854050)
  Regulation of RUNX2 expression and activity (R-HSA-8939902)
  Neddylation (R-HSA-8951664)
  Interleukin-1 signaling (R-HSA-9020702)
  Iron uptake and transport (R-HSA-917937)
  Negative regulation of NOTCH4 signaling (R-HSA-9604323)
  Regulation of BACH1 activity (R-HSA-9708530)
  Nuclear events stimulated by ALK signaling in cancer (R-HSA-9725371)
  GSK3B and BTRC (R-HSA-9762114)
  Antigen processing (R-HSA-983168)
  Activation of NF-kappaB in B cells (R-HSA-1169091)
• BioCyc Pathway: MetaCyc:ENSG00000113558-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Asthma	DISW9QNS	Definitive	Biomarker	[1]
Brugada syndrome	DISSGN0E	Strong	Biomarker	[2]
Deafness	DISKCLH4	Strong	Genetic Variation	[3]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[4]
Late-onset Parkinson disease	DIS9IOUI	Strong	Biomarker	[5]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[6]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[7]
Schizophrenia	DISSRV2N	Strong	Biomarker	[8]
Skin cancer	DISTM18U	Strong	Biomarker	[9]
Ventricular tachycardia	DISIBXJ3	Strong	Biomarker	[2]
Plasma cell myeloma	DIS0DFZ0	moderate	Altered Expression	[10]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[11]
Cutaneous mastocytosis	DISLBZEF	Limited	Biomarker	[12]
facioscapulohumeral muscular dystrophy	DISSE0H0	Limited	Altered Expression	[13]
Huntington disease	DISQPLA4	Limited	Biomarker	[14]
Lung cancer	DISCM4YA	Limited	Biomarker	[15]
Lung carcinoma	DISTR26C	Limited	Biomarker	[15]
Neoplasm	DISZKGEW	Limited	Biomarker	[12]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[16]
Spinocerebellar ataxia type 3	DISQBQID	Limited	Biomarker	[14]
Squamous cell carcinoma	DISQVIFL	Limited	Genetic Variation	[17]
Toxoplasmosis	DISYP8FH	Limited	Biomarker	[18]

2 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 S-phase kinase-associated protein 1 (SKP1).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of S-phase kinase-associated protein 1 (SKP1).	[32]

14 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 S-phase kinase-associated protein 1 (SKP1).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of S-phase kinase-associated protein 1 (SKP1).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of S-phase kinase-associated protein 1 (SKP1).	[22]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of S-phase kinase-associated protein 1 (SKP1).	[23]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of S-phase kinase-associated protein 1 (SKP1).	[24]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of S-phase kinase-associated protein 1 (SKP1).	[25]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of S-phase kinase-associated protein 1 (SKP1).	[26]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of S-phase kinase-associated protein 1 (SKP1).	[27]
Sertraline	DM0FB1J	Approved	Sertraline decreases the expression of S-phase kinase-associated protein 1 (SKP1).	[28]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of S-phase kinase-associated protein 1 (SKP1).	[29]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of S-phase kinase-associated protein 1 (SKP1).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of S-phase kinase-associated protein 1 (SKP1).	[31]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of S-phase kinase-associated protein 1 (SKP1).	[33]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of S-phase kinase-associated protein 1 (SKP1).	[34]

References

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