Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTR957W)

• DOT Name: F-box only protein 5 (FBXO5)
• Synonyms: Early mitotic inhibitor 1
• Gene Name: FBXO5
• Related Disease:
  Breast cancer
  Breast carcinoma
  Hepatocellular carcinoma
  Lung squamous cell carcinoma
  Ovarian neoplasm
  Triple negative breast cancer
  Carcinoma
  Neuroblastoma
• UniProt ID: FBX5_HUMAN
• PDB ID: 2M6N; 4UI9; 7QE7
• Pfam ID: PF00646
• Sequence:
  MSRRPCSCALRPPRCSCSASPSAVTAAGRPRPSDSCKEESSTLSVKMKCDFNCNHVHSGL
  KLVKPDDIGRLVSYTPAYLEGSCKDCIKDYERLSCIGSPIVSPRIVQLETESKRLHNKEN
  QHVQQTLNSTNEIEALETSRLYEDSGYSSFSLQSGLSEHEEGSLLEENFGDSLQSCLLQI
  QSPDQYPNKNLLPVLHFEKVVCSTLKKNAKRNPKVDREMLKEIIARGNFRLQNIIGRKMG
  LECVDILSELFRRGLRHVLATILAQLSDMDLINVSKVSTTWKKILEDDKGAFQLYSKAIQ
  RVTENNNKFSPHASTREYVMFRTPLASVQKSAAQTSLKKDAQTKLSNQGDQKGSTYSRHN
  EFSEVAKTLKKNESLKACIRCNSPAKYDCYLQRATCKREGCGFDYCTKCLCNYHTTKDCS
  DGKLLKASCKIGPLPGTKKSKKNLRRL
• Function: Regulator of APC activity during mitotic and meiotic cell cycle. During mitotic cell cycle plays a role as both substrate and inhibitor of APC-FZR1 complex. During G1 phase, plays a role as substrate of APC-FZR1 complex E3 ligase. Then switches as an inhibitor of APC-FZR1 complex during S and G2 leading to cell-cycle commitment. As APC inhibitor, prevents the degradation of APC substrates at multiple levels: by interacting with APC and blocking access of APC substrates to the D-box coreceptor, formed by FZR1 and ANAPC10; by suppressing ubiquitin ligation and chain elongation by APC by preventing the UBE2C and UBE2S activities. Plays a role in genome integrity preservation by coordinating DNA replication with mitosis through APC inhibition in interphase to stabilize CCNA2 and GMNN in order to promote mitosis and prevent rereplication and DNA damage-induced cellular senescence. During oocyte maturation, plays a role in meiosis through inactivation of APC-FZR1 complex. Inhibits APC through RPS6KA2 interaction that increases FBXO5 affiniy for CDC20 leading to the metaphase arrest of the second meiotic division before fertilization. Controls entry into the first meiotic division through inactivation of APC-FZR1 complex. Promotes migration and osteogenic differentiation of mesenchymal stem cells.
• KEGG Pathway:
  Cell cycle (hsa04110)
  Oocyte meiosis (hsa04114)
• Reactome Pathway:
  Regulation of APC/C activators between G1/S and early anaphase (R-HSA-176408)
  Phosphorylation of Emi1 (R-HSA-176417)
  Mitotic Metaphase/Anaphase Transition (R-HSA-68881)
  G1/S-Specific Transcription (R-HSA-69205)
  SCF-beta-TrCP mediated degradation of Emi1 (R-HSA-174113)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Lung squamous cell carcinoma	DISXPIBD	Strong	Altered Expression	[3]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[4]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	moderate	Biomarker	[6]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[7]

33 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of F-box only protein 5 (FBXO5).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of F-box only protein 5 (FBXO5).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of F-box only protein 5 (FBXO5).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of F-box only protein 5 (FBXO5).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of F-box only protein 5 (FBXO5).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of F-box only protein 5 (FBXO5).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of F-box only protein 5 (FBXO5).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of F-box only protein 5 (FBXO5).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of F-box only protein 5 (FBXO5).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of F-box only protein 5 (FBXO5).	[16]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of F-box only protein 5 (FBXO5).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of F-box only protein 5 (FBXO5).	[17]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of F-box only protein 5 (FBXO5).	[18]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of F-box only protein 5 (FBXO5).	[19]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of F-box only protein 5 (FBXO5).	[20]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of F-box only protein 5 (FBXO5).	[21]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of F-box only protein 5 (FBXO5).	[22]
Paclitaxel	DMLB81S	Approved	Paclitaxel affects the expression of F-box only protein 5 (FBXO5).	[23]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of F-box only protein 5 (FBXO5).	[24]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of F-box only protein 5 (FBXO5).	[25]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of F-box only protein 5 (FBXO5).	[26]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of F-box only protein 5 (FBXO5).	[27]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of F-box only protein 5 (FBXO5).	[28]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of F-box only protein 5 (FBXO5).	[15]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of F-box only protein 5 (FBXO5).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of F-box only protein 5 (FBXO5).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of F-box only protein 5 (FBXO5).	[30]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of F-box only protein 5 (FBXO5).	[31]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of F-box only protein 5 (FBXO5).	[32]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of F-box only protein 5 (FBXO5).	[35]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of F-box only protein 5 (FBXO5).	[36]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of F-box only protein 5 (FBXO5).	[37]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of F-box only protein 5 (FBXO5).	[38]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of F-box only protein 5 (FBXO5).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of F-box only protein 5 (FBXO5).	[34]

References

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