Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJELWK0)

• DOT Name: Cyclin-dependent kinase 5 activator 1 (CDK5R1)
• Synonyms: CDK5 activator 1; Cyclin-dependent kinase 5 regulatory subunit 1; TPKII regulatory subunit
• Gene Name: CDK5R1
• UniProt ID: CD5R1_HUMAN
• PDB ID: 1H4L; 1UNG; 1UNH; 1UNL; 3O0G; 6LDP; 7CNG; 7VDP; 7VDQ; 7VDR; 7VDS
• Pfam ID: PF03261
• Sequence:
  MGTVLSLSPSYRKATLFEDGAATVGHYTAVQNSKNAKDKNLKRHSIISVLPWKRIVAVSA
  KKKNSKKVQPNSSYQNNITHLNNENLKKSLSCANLSTFAQPPPAQPPAPPASQLSGSQTG
  GSSSVKKAPHPAVTSAGTPKRVIVQASTSELLRCLGEFLCRRCYRLKHLSPTDPVLWLRS
  VDRSLLLQGWQDQGFITPANVVFLYMLCRDVISSEVGSDHELQAVLLTCLYLSYSYMGNE
  ISYPLKPFLVESCKEAFWDRCLSVINLMSSKMLQINADPHYFTQVFSDLKNESGQEDKKR
  LLLGLDR
• Function: p35 is a neuron specific activator of CDK5. The complex p35/CDK5 is required for neurite outgrowth and cortical lamination. Involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4 signaling. Activator of TPKII. The complex p35/CDK5 participates in the regulation of the circadian clock by modulating the function of CLOCK protein: phosphorylates CLOCK at 'Thr-451' and 'Thr-461' and regulates the transcriptional activity of the CLOCK-BMAL1 heterodimer in association with altered stability and subcellular distribution.
• Tissue Specificity: Brain and neuron specific.
• KEGG Pathway:
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Cocaine addiction (hsa05030)
• Reactome Pathway:
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models (R-HSA-8862803)
  NGF-stimulated transcription (R-HSA-9031628)
  Activated NTRK2 signals through CDK5 (R-HSA-9032845)
  NPAS4 regulates expression of target genes (R-HSA-9768919)
  CRMPs in Sema3A signaling (R-HSA-399956)

Molecular Interaction Atlas (MIA) of This DOT

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 Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[7]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[3]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[8]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[9]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[8]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea increases the expression of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[8]
Fenretinide	DMRD5SP	Phase 3	Fenretinide decreases the expression of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[10]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the expression of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[8]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[12]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[13]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[14]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl decreases the expression of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[14]
Apicidin	DM83WVF	Investigative	Apicidin decreases the expression of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[8]
Methyl Mercury Ion	DM6YEW4	Investigative	Methyl Mercury Ion decreases the expression of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[14]
Octanedioic acid bis-hydroxyamide	DMJNQ9K	Investigative	Octanedioic acid bis-hydroxyamide decreases the expression of Cyclin-dependent kinase 5 activator 1 (CDK5R1).	[8]

References

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• [2] Effect of all-trans retinoic acid on sodium/iodide symporter expression, radioiodine uptake and gene expression profiles in a human anaplastic thyroid carcinoma cell line. Nucl Med Biol. 2006 Oct;33(7):875-82. doi: 10.1016/j.nucmedbio.2006.07.004.
• [3] Cell-type-specific responses to chemotherapeutics in breast cancer. Cancer Res. 2004 Jun 15;64(12):4218-26.
• [4] Systematic transcriptome-based comparison of cellular adaptive stress response activation networks in hepatic stem cell-derived progeny and primary human hepatocytes. Toxicol In Vitro. 2021 Jun;73:105107. doi: 10.1016/j.tiv.2021.105107. Epub 2021 Feb 3.
• [5] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [6] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [7] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [8] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [9] Cannabidiol Modulates the Expression of Alzheimer's Disease-Related Genes in Mesenchymal Stem Cells. Int J Mol Sci. 2016 Dec 23;18(1):26. doi: 10.3390/ijms18010026.
• [10] 4-HPR modulates gene expression in ovarian cells. Int J Cancer. 2006 Sep 1;119(5):1005-13. doi: 10.1002/ijc.21797.
• [11] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [12] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [13] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [14] Inhibition of CXCL12-mediated chemotaxis of Jurkat cells by direct immunotoxicants. Arch Toxicol. 2016 Jul;90(7):1685-94. doi: 10.1007/s00204-015-1585-7. Epub 2015 Aug 28.