Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVPU04K)

• DOT Name: Coiled-coil and C2 domain-containing protein 1A (CC2D1A)
• Synonyms: Akt kinase-interacting protein 1; Five prime repressor element under dual repression-binding protein 1; FRE under dual repression-binding protein 1; Freud-1; Putative NF-kappa-B-activating protein 023N
• Gene Name: CC2D1A
• Related Disease:
  Complex neurodevelopmental disorder
  Intellectual disability, autosomal recessive 3
  Anxiety
  Anxiety disorder
  Autism
  Autism spectrum disorder
  Cognitive impairment
  Depression
  Epithelial ovarian cancer
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Pervasive developmental disorder
  Neurodevelopmental disorder
  Pancreatic cancer
  Autosomal recessive non-syndromic intellectual disability
  Intellectual disability
  Neuroblastoma
• UniProt ID: C2D1A_HUMAN
• Pfam ID: PF00168 ; PF21528
• Sequence:
  MHKRKGPPGPPGRGAAAARQLGLLVDLSPDGLMIPEDGANDEELEAEFLALVGGQPPALE
  KLKGKGPLPMEAIEKMASLCMRDPDEDEEEGTDEDDLEADDDLLAELNEVLGEEQKASET
  PPPVAQPKPEAPHPGLETTLQERLALYQTAIESARQAGDSAKMRRYDRGLKTLENLLASI
  RKGNAIDEADIPPPVAIGKGPASTPTYSPAPTQPAPRIASAPEPRVTLEGPSATAPASSP
  GLAKPQMPPGPCSPGPLAQLQSRQRDYKLAALHAKQQGDTTAAARHFRVAKSFDAVLEAL
  SRGEPVDLSCLPPPPDQLPPDPPSPPSQPPTPATAPSTTEVPPPPRTLLEALEQRMERYQ
  VAAAQAKSKGDQRKARMHERIVKQYQDAIRAHKAGRAVDVAELPVPPGFPPIQGLEATKP
  TQQSLVGVLETAMKLANQDEGPEDEEDEVPKKQNSPVAPTAQPKAPPSRTPQSGSAPTAK
  APPKATSTRAQQQLAFLEGRKKQLLQAALRAKQKNDVEGAKMHLRQAKGLEPMLEASRNG
  LPVDITKVPPAPVNKDDFALVQRPGPGLSQEAARRYGELTKLIRQQHEMCLNHSNQFTQL
  GNITETTKFEKLAEDCKRSMDILKQAFVRGLPTPTARFEQRTFSVIKIFPDLSSNDMLLF
  IVKGINLPTPPGLSPGDLDVFVRFDFPYPNVEEAQKDKTSVIKNTDSPEFKEQFKLCINR
  SHRGFRRAIQTKGIKFEVVHKGGLFKTDRVLGTAQLKLDALEIACEVREILEVLDGRRPT
  GGRLEVMVRIREPLTAQQLETTTERWLVIDPVPAAVPTQVAGPKGKAPPVPAPARESGNR
  SARPLHSLSVLAFDQERLERKILALRQARRPVPPEVAQQYQDIMQRSQWQRAQLEQGGVG
  IRREYAAQLERQLQFYTEAARRLGNDGSRDAAKEALYRRNLVESELQRLRR
• Function: Transcription factor that binds specifically to the DRE (dual repressor element) and represses HTR1A gene transcription in neuronal cells. The combination of calcium and ATP specifically inactivates the binding with FRE. May play a role in the altered regulation of HTR1A associated with anxiety and major depression. Mediates HDAC-independent repression of HTR1A promoter in neuronal cell. Performs essential function in controlling functional maturation of synapses. Plays distinct roles depending on its localization. When cytoplasmic, acts as a scaffold protein in the PI3K/PDK1/AKT pathway. Repressor of HTR1A when nuclear. In the centrosome, regulates spindle pole localization of the cohesin subunit SCC1/RAD21, thereby mediating centriole cohesion during mitosis.

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal recessive	[1]
Intellectual disability, autosomal recessive 3	DISNX1E9	Definitive	Autosomal recessive	[2]
Anxiety	DISIJDBA	Strong	Altered Expression	[3]
Anxiety disorder	DISBI2BT	Strong	Altered Expression	[3]
Autism	DISV4V1Z	Strong	Biomarker	[4]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[5]
Cognitive impairment	DISH2ERD	Strong	Biomarker	[6]
Depression	DIS3XJ69	Strong	Biomarker	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[7]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[7]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[7]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[5]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[8]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[9]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[2]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[10]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[11]

3 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 Coiled-coil and C2 domain-containing protein 1A (CC2D1A).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Coiled-coil and C2 domain-containing protein 1A (CC2D1A).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Coiled-coil and C2 domain-containing protein 1A (CC2D1A).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Coiled-coil and C2 domain-containing protein 1A (CC2D1A).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Coiled-coil and C2 domain-containing protein 1A (CC2D1A).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Coiled-coil and C2 domain-containing protein 1A (CC2D1A).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Coiled-coil and C2 domain-containing protein 1A (CC2D1A).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Coiled-coil and C2 domain-containing protein 1A (CC2D1A).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Coiled-coil and C2 domain-containing protein 1A (CC2D1A).	[19]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Coiled-coil and C2 domain-containing protein 1A (CC2D1A).	[21]

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] The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive non-syndromic mental retardation. J Med Genet. 2006 Mar;43(3):203-10. doi: 10.1136/jmg.2005.035709. Epub 2005 Jul 20.
• [3] Abrogated Freud-1/Cc2d1a Repression of 5-HT1A Autoreceptors Induces Fluoxetine-Resistant Anxiety/Depression-Like Behavior.J Neurosci. 2017 Dec 6;37(49):11967-11978. doi: 10.1523/JNEUROSCI.1668-17.2017. Epub 2017 Nov 3.
• [4] Disregulation of Autophagy in the Transgenerational Cc2d1a Mouse Model of Autism.Neuromolecular Med. 2020 Jun;22(2):239-249. doi: 10.1007/s12017-019-08579-x. Epub 2019 Nov 13.
• [5] Male-Specific cAMP Signaling in the Hippocampus Controls Spatial Memory Deficits in a Mouse Model of Autism and Intellectual Disability.Biol Psychiatry. 2019 May 1;85(9):760-768. doi: 10.1016/j.biopsych.2018.12.013. Epub 2018 Dec 27.
• [6] Conditional Deletion of CC2D1A Reduces Hippocampal Synaptic Plasticity and Impairs Cognitive Function through Rac1 Hyperactivation.J Neurosci. 2019 Jun 19;39(25):4959-4975. doi: 10.1523/JNEUROSCI.2395-18.2019. Epub 2019 Apr 16.
• [7] Coiled-Coil and C2 Domain-Containing Protein 1A (CC2D1A) Promotes Chemotherapy Resistance in Ovarian Cancer.Front Oncol. 2019 Oct 1;9:986. doi: 10.3389/fonc.2019.00986. eCollection 2019.
• [8] Cc2d1a Loss of Function Disrupts Functional and Morphological Development in Forebrain Neurons Leading to Cognitive and Social Deficits.Cereb Cortex. 2017 Feb 1;27(2):1670-1685. doi: 10.1093/cercor/bhw009.
• [9] Expression of Akt kinase-interacting protein 1, a scaffold protein of the PI3K/PDK1/Akt pathway, in pancreatic cancer.Pancreas. 2014 Oct;43(7):1093-100. doi: 10.1097/MPA.0000000000000168.
• [10] Recruitment by the Repressor Freud-1 of Histone Deacetylase-Brg1 Chromatin Remodeling Complexes to Strengthen HTR1A Gene Repression.Mol Neurobiol. 2017 Dec;54(10):8263-8277. doi: 10.1007/s12035-016-0306-4. Epub 2016 Dec 2.
• [11] 17-estradiol-induced regulation of the novel 5-HT1A-related transcription factors NUDR and Freud-1 in SH SY5Y cells.Cell Mol Neurobiol. 2012 May;32(4):517-21. doi: 10.1007/s10571-012-9809-3. Epub 2012 Feb 11.
• [12] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [13] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [14] 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.
• [15] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [16] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [17] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [18] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] 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.
• [21] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.