Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGL5HRV)

• DOT Name: Cyclin-dependent kinase-like 5 (CDKL5)
• Synonyms: EC 2.7.11.22; Serine/threonine-protein kinase 9
• Gene Name: CDKL5
• Related Disease:
  CDKL5 disorder
  Craniodiaphyseal dysplasia
  Craniodiaphyseal dysplasia, autosomal dominant
  Developmental and epileptic encephalopathy, 2
  Inherited retinal dystrophy
  Intellectual disability
  Nervous system disease
  Angelman syndrome
  Attention deficit hyperactivity disorder
  Epileptic encephalopathy
  Infantile epileptic-dyskinetic encephalopathy
  Methylmalonic acidemia
  Parkinson disease
  Sleep apnea syndrome
  Sleep disorder
  X-linked retinoschisis
  Autism spectrum disorder
  Isolated congenital microcephaly
  Mental disorder
  Atypical Rett syndrome
  Infantile spasm
  West syndrome
  Atrial septal defect
  Hearing loss, X-linked 4
  Megalencephaly
  Neuroblastoma
  Orofaciodigital syndrome I
  Precocious puberty
  Sensorineural hearing loss disorder
• UniProt ID: CDKL5_HUMAN
• PDB ID: 4BGQ; 8CIE
• EC Number: 2.7.11.22
• Pfam ID: PF00069
• Sequence:
  MKIPNIGNVMNKFEILGVVGEGAYGVVLKCRHKETHEIVAIKKFKDSEENEEVKETTLRE
  LKMLRTLKQENIVELKEAFRRRGKLYLVFEYVEKNMLELLEEMPNGVPPEKVKSYIYQLI
  KAIHWCHKNDIVHRDIKPENLLISHNDVLKLCDFGFARNLSEGNNANYTEYVATRWYRSP
  ELLLGAPYGKSVDMWSVGCILGELSDGQPLFPGESEIDQLFTIQKVLGPLPSEQMKLFYS
  NPRFHGLRFPAVNHPQSLERRYLGILNSVLLDLMKNLLKLDPADRYLTEQCLNHPTFQTQ
  RLLDRSPSRSAKRKPYHVESSTLSNRNQAGKSTALQSHHRSNSKDIQNLSVGLPRADEGL
  PANESFLNGNLAGASLSPLHTKTYQASSQPGSTSKDLTNNNIPHLLSPKEAKSKTEFDFN
  IDPKPSEGPGTKYLKSNSRSQQNRHSFMESSQSKAGTLQPNEKQSRHSYIDTIPQSSRSP
  SYRTKAKSHGALSDSKSVSNLSEARAQIAEPSTSRYFPSSCLDLNSPTSPTPTRHSDTRT
  LLSPSGRNNRNEGTLDSRRTTTRHSKTMEELKLPEHMDSSHSHSLSAPHESFSYGLGYTS
  PFSSQQRPHRHSMYVTRDKVRAKGLDGSLSIGQGMAARANSLQLLSPQPGEQLPPEMTVA
  RSSVKETSREGTSSFHTRQKSEGGVYHDPHSDDGTAPKENRHLYNDPVPRRVGSFYRVPS
  PRPDNSFHENNVSTRVSSLPSESSSGTNHSKRQPAFDPWKSPENISHSEQLKEKEKQGFF
  RSMKKKKKKSQTVPNSDSPDLLTLQKSIHSASTPSSRPKEWRPEKISDLQTQSQPLKSLR
  KLLHLSSASNHPASSDPRFQPLTAQQTKNSFSEIRIHPLSQASGGSSNIRQEPAPKGRPA
  LQLPGQMDPGWHVSSVTRSATEGPSYSEQLGAKSGPNGHPYNRTNRSRMPNLNDLKETAL
• Function: Mediates phosphorylation of MECP2. May regulate ciliogenesis.
• Tissue Specificity: Expressed in brain, lung, kidney, prostate, ovary, placenta, pancreas and testis.; [Isoform 2]: Predominant transcript in brain.

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
CDKL5 disorder	DIS2OAEX	Definitive	X-linked	[1]
Craniodiaphyseal dysplasia	DIST8T27	Definitive	Genetic Variation	[2]
Craniodiaphyseal dysplasia, autosomal dominant	DIS2YXJ1	Definitive	Genetic Variation	[2]
Developmental and epileptic encephalopathy, 2	DISTFDNW	Definitive	X-linked	[3]
Inherited retinal dystrophy	DISGGL77	Definitive	CausalMutation	[4]
Intellectual disability	DISMBNXP	Definitive	Genetic Variation	[5]
Nervous system disease	DISJ7GGT	Definitive	Genetic Variation	[6]
Angelman syndrome	DIS4QVXO	Strong	Genetic Variation	[7]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[8]
Epileptic encephalopathy	DISZOCA3	Strong	GermlineCausalMutation	[9]
Infantile epileptic-dyskinetic encephalopathy	DISD2ZNC	Strong	Genetic Variation	[10]
Methylmalonic acidemia	DISHY8VB	Strong	Biomarker	[11]
Parkinson disease	DISQVHKL	Strong	Biomarker	[12]
Sleep apnea syndrome	DISER6KS	Strong	Biomarker	[13]
Sleep disorder	DIS3JP1U	Strong	Genetic Variation	[14]
X-linked retinoschisis	DISKV7Y8	Strong	Genetic Variation	[15]
Autism spectrum disorder	DISXK8NV	moderate	Biomarker	[16]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[17]
Mental disorder	DIS3J5R8	moderate	Biomarker	[18]
Atypical Rett syndrome	DISWF699	Supportive	Autosomal dominant	[9]
Infantile spasm	DISZSKDG	Supportive	Autosomal dominant	[9]
West syndrome	DISLIAU9	Supportive	Autosomal dominant	[19]
Atrial septal defect	DISJT76B	Limited	Biomarker	[16]
Hearing loss, X-linked 4	DISECS9M	Limited	Genetic Variation	[20]
Megalencephaly	DISYW5SV	Limited	Biomarker	[21]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[22]
Orofaciodigital syndrome I	DIST27XL	Limited	Genetic Variation	[20]
Precocious puberty	DISYI2XZ	Limited	X-linked	[23]
Sensorineural hearing loss disorder	DISJV45Z	Limited	Genetic Variation	[20]

10 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-like 5 (CDKL5).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cyclin-dependent kinase-like 5 (CDKL5).	[25]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cyclin-dependent kinase-like 5 (CDKL5).	[26]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Cyclin-dependent kinase-like 5 (CDKL5).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cyclin-dependent kinase-like 5 (CDKL5).	[28]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Cyclin-dependent kinase-like 5 (CDKL5).	[29]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Cyclin-dependent kinase-like 5 (CDKL5).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cyclin-dependent kinase-like 5 (CDKL5).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Cyclin-dependent kinase-like 5 (CDKL5).	[32]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cyclin-dependent kinase-like 5 (CDKL5).	[33]

References

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• [2] Pharmacotherapy with sertraline rescues brain development and behavior in a mouse model of CDKL5 deficiency disorder.Neuropharmacology. 2020 May 1;167:107746. doi: 10.1016/j.neuropharm.2019.107746. Epub 2019 Aug 27.
• [3] Wide range of phenotypic severity in individuals with late truncations unique to the predominant CDKL5 transcript in the brain. Am J Med Genet A. 2022 Dec;188(12):3516-3524. doi: 10.1002/ajmg.a.62940. Epub 2022 Aug 7.
• [4] Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease.Ophthalmology. 2016 May;123(5):1143-50. doi: 10.1016/j.ophtha.2016.01.009. Epub 2016 Feb 9.
• [5] AMPA Receptor Dysregulation and Therapeutic Interventions in a Mouse Model of CDKL5 Deficiency Disorder.J Neurosci. 2019 Jun 12;39(24):4814-4828. doi: 10.1523/JNEUROSCI.2041-18.2019. Epub 2019 Apr 5.
• [6] The antidepressant tianeptine reverts synaptic AMPA receptor defects caused by deficiency of CDKL5.Hum Mol Genet. 2018 Jun 15;27(12):2052-2063. doi: 10.1093/hmg/ddy108.
• [7] Genetic disorders associated with postnatal microcephaly.Am J Med Genet C Semin Med Genet. 2014 Jun;166C(2):140-55. doi: 10.1002/ajmg.c.31400. Epub 2014 May 16.
• [8] Mice lacking cyclin-dependent kinase-like 5 manifest autistic and ADHD-like behaviors.Hum Mol Genet. 2017 Oct 15;26(20):3922-3934. doi: 10.1093/hmg/ddx279.
• [9] Genes of early-onset epileptic encephalopathies: from genotype to phenotype. Pediatr Neurol. 2012 Jan;46(1):24-31. doi: 10.1016/j.pediatrneurol.2011.11.003.
• [10] Clinical evolution and epilepsy outcome in three patients with CDKL5-related developmental encephalopathy.Epileptic Disord. 2019 Jun 1;21(3):271-277. doi: 10.1684/epd.2019.1071.
• [11] A male case with CDKL5-associated encephalopathy manifesting transient methylmalonic acidemia.Eur J Med Genet. 2018 Aug;61(8):451-454. doi: 10.1016/j.ejmg.2018.03.003. Epub 2018 Mar 3.
• [12] Kinases in synaptic development and neurological diseases.Prog Neuropsychopharmacol Biol Psychiatry. 2018 Jun 8;84(Pt B):343-352. doi: 10.1016/j.pnpbp.2017.12.006. Epub 2017 Dec 11.
• [13] CDKL5 deficiency entails sleep apneas in mice.J Sleep Res. 2017 Aug;26(4):495-497. doi: 10.1111/jsr.12512. Epub 2017 Feb 23.
• [14] Respiratory and sleep disorders in female children with atypical Rett syndrome caused by mutations in the CDKL5 gene.Dev Med Child Neurol. 2013 May;55(5):480-4. doi: 10.1111/j.1469-8749.2012.04432.x. Epub 2012 Nov 14.
• [15] Genetic analysis and clinical features of X-linked retinoschisis in Chinese patients.Sci Rep. 2017 Mar 8;7:44060. doi: 10.1038/srep44060.
• [16] Deep learning of spontaneous arousal fluctuations detects early cholinergic defects across neurodevelopmental mouse models and patients.Proc Natl Acad Sci U S A. 2020 Sep 22;117(38):23298-23303. doi: 10.1073/pnas.1820847116. Epub 2019 Jul 22.
• [17] Revisiting the phenotype associated with FOXG1 mutations: two novel cases of congenital Rett variant.Neurogenetics. 2010 May;11(2):241-9. doi: 10.1007/s10048-009-0220-2. Epub 2009 Oct 6.
• [18] Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.Cell. 2012 Apr 27;149(3):525-37. doi: 10.1016/j.cell.2012.03.028. Epub 2012 Apr 19.
• [19] CDKL5 disruption by t(X;18) in a girl with West syndrome. Clin Genet. 2008 Sep;74(3):288-90. doi: 10.1111/j.1399-0004.2008.01048.x. Epub 2008 Jun 28.
• [20] Identification and characterization of a novel serine-threonine kinase gene from the Xp22 region.Genomics. 1998 Aug 1;51(3):427-33. doi: 10.1006/geno.1998.5391.
• [21] Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications.Eur J Hum Genet. 2015 Jul;23(7):915-21. doi: 10.1038/ejhg.2014.217. Epub 2014 Oct 15.
• [22] CDKL5, a novel MYCN-repressed gene, blocks cell cycle and promotes differentiation of neuronal cells.Biochim Biophys Acta. 2012 Nov-Dec;1819(11-12):1173-85. doi: 10.1016/j.bbagrm.2012.08.001. Epub 2012 Aug 19.
• [23] 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.
• [24] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [25] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [26] Analysis of the in vitro synergistic effect of 5-fluorouracil and cisplatin on cervical carcinoma cells. Int J Gynecol Cancer. 2006 May-Jun;16(3):1321-9.
• [27] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [28] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [29] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [30] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [31] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [32] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [33] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.