Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX1C2GS)

• DOT Name: Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3)
• Synonyms: EC 2.7.12.1; Regulatory erythroid kinase; REDK
• Gene Name: DYRK3
• UniProt ID: DYRK3_HUMAN
• PDB ID: 5Y86
• EC Number: 2.7.12.1
• Pfam ID: PF00069
• Sequence:
  MGGTARGPGRKDAGPPGAGLPPQQRRLGDGVYDTFMMIDETKCPPCSNVLCNPSEPPPPR
  RLNMTTEQFTGDHTQHFLDGGEMKVEQLFQEFGNRKSNTIQSDGISDSEKCSPTVSQGKS
  SDCLNTVKSNSSSKAPKVVPLTPEQALKQYKHHLTAYEKLEIINYPEIYFVGPNAKKRHG
  VIGGPNNGGYDDADGAYIHVPRDHLAYRYEVLKIIGKGSFGQVARVYDHKLRQYVALKMV
  RNEKRFHRQAAEEIRILEHLKKQDKTGSMNVIHMLESFTFRNHVCMAFELLSIDLYELIK
  KNKFQGFSVQLVRKFAQSILQSLDALHKNKIIHCDLKPENILLKHHGRSSTKVIDFGSSC
  FEYQKLYTYIQSRFYRAPEIILGSRYSTPIDIWSFGCILAELLTGQPLFPGEDEGDQLAC
  MMELLGMPPPKLLEQSKRAKYFINSKGIPRYCSVTTQADGRVVLVGGRSRRGKKRGPPGS
  KDWGTALKGCDDYLFIEFLKRCLHWDPSARLTPAQALRHPWISKSVPRPLTTIDKVSGKR
  VVNPASAFQGLGSKLPPVVGIANKLKANLMSETNGSIPLCSVLPKLIS
• Function: Dual-specificity protein kinase that promotes disassembly of several types of membraneless organelles during mitosis, such as stress granules, nuclear speckles and pericentriolar material. Dual-specificity tyrosine-regulated kinases (DYRKs) autophosphorylate a critical tyrosine residue in their activation loop and phosphorylate their substrate on serine and threonine residues. Acts as a central dissolvase of membraneless organelles during the G2-to-M transition, after the nuclear-envelope breakdown: acts by mediating phosphorylation of multiple serine and threonine residues in unstructured domains of proteins, such as SRRM1 and PCM1. Does not mediate disassembly of all membraneless organelles: disassembly of P-body and nucleolus is not regulated by DYRK3. Dissolution of membraneless organelles at the onset of mitosis is also required to release mitotic regulators, such as ZNF207, from liquid-unmixed organelles where they are sequestered and keep them dissolved during mitosis. Regulates mTORC1 by mediating the dissolution of stress granules: during stressful conditions, DYRK3 partitions from the cytosol to the stress granule, together with mTORC1 components, which prevents mTORC1 signaling. When stress signals are gone, the kinase activity of DYRK3 is required for the dissolution of stress granule and mTORC1 relocation to the cytosol: acts by mediating the phosphorylation of the mTORC1 inhibitor AKT1S1, allowing full reactivation of mTORC1 signaling. Also acts as a negative regulator of EPO-dependent erythropoiesis: may place an upper limit on red cell production during stress erythropoiesis. Inhibits cell death due to cytokine withdrawal in hematopoietic progenitor cells. Promotes cell survival upon genotoxic stress through phosphorylation of SIRT1: this in turn inhibits p53/TP53 activity and apoptosis.
• Tissue Specificity: Isoform 1: Highly expressed in testis and in hematopoietic tissue such as fetal liver, and bone marrow . Isoform 1: Predominant form in fetal liver and bone marrow . Isoform 1: Present at low levels in heart, pancreas, lymph node and thymus . Isoform 2: Highly expressed in testis and in hematopoietic tissue such as fetal liver, and bone marrow . Isoform 2: Predominant form in testis. Isoform 2: Present at low levels in heart, pancreas, lymph node and thymus .

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[15]
Oxamflatin	DM1TG3C	Terminated	Oxamflatin increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[17]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[18]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[11]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[19]
Apicidin	DM83WVF	Investigative	Apicidin increases the expression of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3).	[16]

References

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• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] 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.
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• [17] 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.
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• [19] 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.