Details of Drug Off-Target (DOT)

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

• DOT Name: CDK5 regulatory subunit-associated protein 2 (CDK5RAP2)
• Synonyms: CDK5 activator-binding protein C48; Centrosome-associated protein 215
• Gene Name: CDK5RAP2
• Related Disease:
  Autosomal recessive primary microcephaly
  Alzheimer disease
  Chronic eosinophilic leukemia
  Isolated congenital microcephaly
  Microcephaly 3, primary, autosomal recessive
  Rheumatoid arthritis
  Sensorineural hearing loss disorder
  Advanced cancer
  Corpus callosum, agenesis of
  Intellectual disability
  Microphthalmia
• UniProt ID: CK5P2_HUMAN
• PDB ID: 6X0V
• Pfam ID: PF07989
• Sequence:
  MMDLVLEEDVTVPGTLSGCSGLVPSVPDDLDGINPNAGLGNGLLPNVSEETVSPTRARNM
  KDFENQITELKKENFNLKLRIYFLEERMQQEFHGPTEHIYKTNIELKVEVESLKRELQER
  EQLLIKASKAVESLAEAGGSEIQRVKEDARKKVQQVEDLLTKRILLLEKDVTAAQAELEK
  AFAGTETEKALRLRLESKLSEMKKMHEGDLAMALVLDEKDRLIEELKLSLKSKEALIQCL
  KEEKSQMACPDENVSSGELRGLCAAPREEKERETEAAQMEHQKERNSFEERIQALEEDLR
  EKEREIATEKKNSLKRDKAIQGLTMALKSKEKKVEELNSEIEKLSAAFAKAREALQKAQT
  QEFQGSEDYETALSGKEALSAALRSQNLTKSTENHRLRRSIKKITQELSDLQQERERLEK
  DLEEAHREKSKGDCTIRDLRNEVEKLRNEVNEREKAMENRYKSLLSESNKKLHNQEQVIK
  HLTESTNQKDVLLQKFNEKDLEVIQQNCYLMAAEDLELRSEGLITEKCSSQQPPGSKTIF
  SKEKKQSSDYEELIQVLKKEQDIYTHLVKSLQESDSINNLQAELNKIFALRKQLEQDVLS
  YQNLRKTLEEQISEIRRREEESFSLYSDQTSYLSICLEENNRFQVEHFSQEELKKKVSDL
  IQLVKELYTDNQHLKKTIFDLSCMGFQGNGFPDRLASTEQTELLASKEDEDTIKIGEDDE
  INFLSDQHLQQSNEIMKDLSKGGCKNGYLRHTESKISDCDGAHAPGCLEEGAFINLLAPL
  FNEKATLLLESRPDLLKVVRELLLGQLFLTEQEVSGEHLDGKTEKTPKQKGELVHFVQTN
  SFSKPHDELKLSCEAQLVKAGEVPKVGLKDASVQTVATEGDLLRFKHEATREAWEEKPIN
  TALSAEHRPENLHGVPGWQAALLSLPGITNREAKKSRLPILIKPSRSLGNMYRLPATQEV
  VTQLQSQILELQGELKEFKTCNKQLHQKLILAEAVMEGRPTPDKTLLNAQPPVGAAYQDS
  PGEQKGIKTTSSVWRDKEMDSDQQRSYEIDSEICPPDDLASLPSCKENPEDVLSPTSVAT
  YLSSKSQPSAKVSVMGTDQSESINTSNETEYLKQKIHDLETELEGYQNFIFQLQKHSQCS
  EAIITVLCGTEGAQDGLSKPKNGSDGEEMTFSSLHQVRYVKHVKILGPLAPEMIDSRVLE
  NLKQQLEEQEYKLQKEQNLNMQLFSEIHNLQNKFRDLSPPRYDSLVQSQARELSLQRQQI
  KDGHGICVISRQHMNTMIKAFEELLQASDVDYCVAEGFQEQLNQCAELLEKLEKLFLNGK
  SVGVEMNTQNELMERIEEDNLTYQHLLPESPEPSASHALSDYETSEKSFFSRDQKQDNET
  EKTSVMVNSFSQDLLMEHIQEIRTLRKRLEESIKTNEKLRKQLERQGSEFVQGSTSIFAS
  GSELHSSLTSEIHFLRKQNQALNAMLIKGSRDKQKENDKLRESLSRKTVSLEHLQREYAS
  VKEENERLQKEGSEKERHNQQLIQEVRCSGQELSRVQEEVKLRQQLLSQNDKLLQSLRVE
  LKAYEKLDEEHRRLREASGEGWKGQDPFRDLHSLLMEIQALRLQLERSIETSSTLQSRLK
  EQLARGAEKAQEGALTLAVQAVSIPEVPLQPDKHDGDKYPMESDNSFDLFDSSQAVTPKS
  VSETPPLSGNDTDSLSCDSGSSATSTPCVSRLVTGHHLWASKNGRHVLGLIEDYEALLKQ
  ISQGQRLLAEMDIQTQEAPSSTSQELGTKGPHPAPLSKFVSSVSTAKLTLEEAYRRLKLL
  WRVSLPEDGQCPLHCEQIGEMKAEVTKLHKKLFEQEKKLQNTMKLLQLSKRQEKVIFDQL
  VVTHKILRKARGNLELRPGGAHPGTCSPSRPGS
• Function: Potential regulator of CDK5 activity via its interaction with CDK5R1. Negative regulator of centriole disengagement (licensing) which maintains centriole engagement and cohesion. Involved in regulation of mitotic spindle orientation. Plays a role in the spindle checkpoint activation by acting as a transcriptional regulator of both BUBR1 and MAD2 promoter. Together with EB1/MAPRE1, may promote microtubule polymerization, bundle formation, growth and dynamics at the plus ends. Regulates centrosomal maturation by recruitment of the gamma-tubulin ring complex (gamma-TuRC) onto centrosomes. In complex with PDE4DIP isoform 13/MMG8/SMYLE, MAPRE1 and AKAP9, contributes to microtubules nucleation and extension from the centrosome to the cell periphery. Required for the recruitment of AKAP9 to centrosomes. Plays a role in neurogenesis.
• Tissue Specificity: Widely expressed. Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
• Reactome Pathway:
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  AURKA Activation by TPX2 (R-HSA-8854518)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive primary microcephaly	DIS29IE3	Definitive	Autosomal recessive	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Chronic eosinophilic leukemia	DISAJOUO	Strong	Genetic Variation	[3]
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[4]
Microcephaly 3, primary, autosomal recessive	DISQPO4L	Strong	Autosomal recessive	[5]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[6]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[4]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[7]
Corpus callosum, agenesis of	DISO9P40	Limited	Autosomal recessive	[8]
Intellectual disability	DISMBNXP	Limited	Biomarker	[9]
Microphthalmia	DISGEBES	Limited	Biomarker	[10]

14 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 CDK5 regulatory subunit-associated protein 2 (CDK5RAP2).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of CDK5 regulatory subunit-associated protein 2 (CDK5RAP2).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of CDK5 regulatory subunit-associated protein 2 (CDK5RAP2).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of CDK5 regulatory subunit-associated protein 2 (CDK5RAP2).	[14]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of CDK5 regulatory subunit-associated protein 2 (CDK5RAP2).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of CDK5 regulatory subunit-associated protein 2 (CDK5RAP2).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of CDK5 regulatory subunit-associated protein 2 (CDK5RAP2).	[17]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of CDK5 regulatory subunit-associated protein 2 (CDK5RAP2).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of CDK5 regulatory subunit-associated protein 2 (CDK5RAP2).	[19]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone decreases the expression of CDK5 regulatory subunit-associated protein 2 (CDK5RAP2).	[20]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of CDK5 regulatory subunit-associated protein 2 (CDK5RAP2).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of CDK5 regulatory subunit-associated protein 2 (CDK5RAP2).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of CDK5 regulatory subunit-associated protein 2 (CDK5RAP2).	[23]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of CDK5 regulatory subunit-associated protein 2 (CDK5RAP2).	[26]

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 increases the phosphorylation of CDK5 regulatory subunit-associated protein 2 (CDK5RAP2).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of CDK5 regulatory subunit-associated protein 2 (CDK5RAP2).	[25]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] CDK5RAP2 gene and tau pathophysiology in late-onset sporadic Alzheimer's disease.Alzheimers Dement. 2018 Jun;14(6):787-796. doi: 10.1016/j.jalz.2017.12.004. Epub 2018 Jan 19.
• [3] Transient response to imatinib in a chronic eosinophilic leukemia associated with ins(9;4)(q33;q12q25) and a CDK5RAP2-PDGFRA fusion gene.Genes Chromosomes Cancer. 2006 Oct;45(10):950-6. doi: 10.1002/gcc.20359.
• [4] A new association between CDK5RAP2 microcephaly and congenital cataracts.Ann Hum Genet. 2018 May;82(3):165-170. doi: 10.1111/ahg.12232. Epub 2017 Dec 22.
• [5] CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects. J Med Genet. 2020 Jun;57(6):389-399. doi: 10.1136/jmedgenet-2019-106474. Epub 2020 Feb 3.
• [6] Novel risk loci for rheumatoid arthritis in Han Chinese and congruence with risk variants in Europeans.Arthritis Rheumatol. 2014 May;66(5):1121-32. doi: 10.1002/art.38353.
• [7] A CEP215-HSET complex links centrosomes with spindle poles and drives centrosome clustering in cancer.Nat Commun. 2016 Mar 18;7:11005. doi: 10.1038/ncomms11005.
• [8] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [9] Species-Specific Expression of Full-Length and Alternatively Spliced Variant Forms of CDK5RAP2.PLoS One. 2015 Nov 9;10(11):e0142577. doi: 10.1371/journal.pone.0142577. eCollection 2015.
• [10] Congenital microcephaly-linked CDK5RAP2 affects eye development.Ann Hum Genet. 2020 Jan;84(1):87-91. doi: 10.1111/ahg.12343. Epub 2019 Jul 29.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [13] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 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.
• [16] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [17] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [18] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Unique bisphenol A transcriptome in prostate cancer: novel effects on ERbeta expression that correspond to androgen receptor mutation status. Environ Health Perspect. 2007 Nov;115(11):1646-53. doi: 10.1289/ehp.10283.
• [21] Anti-proliferative and gene expression actions of resveratrol in breast cancer cells in vitro. Oncotarget. 2014 Dec 30;5(24):12891-907.
• [22] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [23] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [24] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [25] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [26] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.