Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT90YSM5)

• DOT Name: Tau-tubulin kinase 2 (TTBK2)
• Synonyms: EC 2.7.11.1
• Gene Name: TTBK2
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Cardiac arrest
  Cerebellar ataxia
  Glioma
  Movement disorder
  Neoplasm
  Renal carcinoma
  Renal cell carcinoma
  Spinocerebellar ataxia type 11
  Autosomal dominant cerebellar ataxia type II
  Spinocerebellar ataxia type 1
  Amyotrophic lateral sclerosis
  Frontotemporal dementia
  Spinocerebellar ataxia type 2
  Spinocerebellar ataxia type 5
  Spinocerebellar ataxia type 6
  Tauopathy
• UniProt ID: TTBK2_HUMAN
• PDB ID: 6U0K; 6VRF; 7O3B; 7Q8Y; 7Q8Z; 7Q90
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MSGGGEQLDILSVGILVKERWKVLRKIGGGGFGEIYDALDMLTRENVALKVESAQQPKQV
  LKMEVAVLKKLQGKDHVCRFIGCGRNDRFNYVVMQLQGRNLADLRRSQSRGTFTISTTLR
  LGRQILESIESIHSVGFLHRDIKPSNFAMGRFPSTCRKCYMLDFGLARQFTNSCGDVRPP
  RAVAGFRGTVRYASINAHRNREMGRHDDLWSLFYMLVEFVVGQLPWRKIKDKEQVGSIKE
  RYDHRLMLKHLPPEFSIFLDHISSLDYFTKPDYQLLTSVFDNSIKTFGVIESDPFDWEKT
  GNDGSLTTTTTSTTPQLHTRLTPAAIGIANATPIPGDLLRENTDEVFPDEQLSDGENGIP
  VGVSPDKLPGSLGHPRPQEKDVWEEMDANKNKIKLGICKAATEEENSHGQANGLLNAPSL
  GSPIRVRSEITQPDRDIPLVRKLRSIHSFELEKRLTLEPKPDTDKFLETCLEKMQKDTSA
  GKESILPALLHKPCVPAVSRTDHIWHYDEEYLPDASKPASANTPEQADGGGSNGFIAVNL
  SSCKQEIDSKEWVIVDKEQDLQDFRTNEAVGHKTTGSPSDEEPEVLQVLEASPQDEKLQL
  GPWAENDHLKKETSGVVLALSAEGPPTAASEQYTDRLELQPGAASQFIAATPTSLMEAQA
  EGPLTAITIPRPSVASTQSTSGSFHCGQQPEKKDLQPMEPTVELYSPRENFSGLVVTEGE
  PPSGGSRTDLGLQIDHIGHDMLPNIRESNKSQDLGPKELPDHNRLVVREFENLPGETEEK
  SILLESDNEDEKLSRGQHCIEISSLPGDLVIVEKDHSATTEPLDVTKTQTFSVVPNQDKN
  NEIMKLLTVGTSEISSRDIDPHVEGQIGQVAEMQKNKISKDDDIMSEDLPGHQGDLSTFL
  HQEGKREKITPRNGELFHCVSENEHGAPTRKDMVRSSFVTRHSRIPVLAQEIDSTLESSS
  PVSAKEKLLQKKAYQPDLVKLLVEKRQFKSFLGDLSSASDKLLEEKLATVPAPFCEEEVL
  TPFSRLTVDSHLSRSAEDSFLSPIISQSRKSKIPRPVSWVNTDQVNSSTSSQFFPRPPPG
  KPPTRPGVEARLRRYKVLGSSNSDSDLFSRLAQILQNGSQKPRSTTQCKSPGSPHNPKTP
  PKSPVVPRRSPSASPRSSSLPRTSSSSPSRAGRPHHDQRSSSPHLGRSKSPPSHSGSSSS
  RRSCQQEHCKPSKNGLKGSGSLHHHSASTKTPQGKSKPASKLSR
• Function: Serine/threonine kinase that acts as a key regulator of ciliogenesis: controls the initiation of ciliogenesis by binding to the distal end of the basal body and promoting the removal of CCP110, which caps the mother centriole, leading to the recruitment of IFT proteins, which build the ciliary axoneme. Has some substrate preference for proteins that are already phosphorylated on a Tyr residue at the +2 position relative to the phosphorylation site. Able to phosphorylate tau on serines in vitro. Phosphorylates MPHOSPH9 which promotes its ubiquitination and proteasomal degradation, loss of MPHOSPH9 facilitates the removal of the CP110-CEP97 complex (a negative regulator of ciliogenesis) from the mother centrioles, promoting the initiation of ciliogenesis.
• Reactome Pathway: Anchoring of the basal body to the plasma membrane (R-HSA-5620912)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Cardiac arrest	DIS9DIA4	Strong	Genetic Variation	[3]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[1]
Movement disorder	DISOJJ2D	Strong	Genetic Variation	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Renal carcinoma	DISER9XT	Strong	Altered Expression	[5]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[5]
Spinocerebellar ataxia type 11	DISKF7FQ	Strong	Autosomal dominant	[6]
Autosomal dominant cerebellar ataxia type II	DIS0PM39	Disputed	Biomarker	[6]
Spinocerebellar ataxia type 1	DISF7BO2	Disputed	Biomarker	[6]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[7]
Frontotemporal dementia	DISKYHXL	Limited	Altered Expression	[7]
Spinocerebellar ataxia type 2	DISF7WDI	Limited	Biomarker	[6]
Spinocerebellar ataxia type 5	DISPYXJ0	Limited	Biomarker	[6]
Spinocerebellar ataxia type 6	DISH7224	Limited	Biomarker	[6]
Tauopathy	DISY2IPA	Limited	Biomarker	[8]

10 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 Tau-tubulin kinase 2 (TTBK2).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Tau-tubulin kinase 2 (TTBK2).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Tau-tubulin kinase 2 (TTBK2).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Tau-tubulin kinase 2 (TTBK2).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Tau-tubulin kinase 2 (TTBK2).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Tau-tubulin kinase 2 (TTBK2).	[14]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Tau-tubulin kinase 2 (TTBK2).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Tau-tubulin kinase 2 (TTBK2).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Tau-tubulin kinase 2 (TTBK2).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Tau-tubulin kinase 2 (TTBK2).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Tau-tubulin kinase 2 (TTBK2).	[16]

References

• [1] TTBK2 circular RNA promotes glioma malignancy by regulating miR-217/HNF1/Derlin-1 pathway.J Hematol Oncol. 2017 Feb 20;10(1):52. doi: 10.1186/s13045-017-0422-2.
• [2] Caenorhabditis elegans hub genes that respond to amyloid beta are homologs of genes involved in human Alzheimer's disease.PLoS One. 2019 Jul 10;14(7):e0219486. doi: 10.1371/journal.pone.0219486. eCollection 2019.
• [3] Spinocerebellar ataxia type 11 in the Chinese Han population.Neurol Sci. 2010 Feb;31(1):107-9. doi: 10.1007/s10072-009-0129-4. Epub 2009 Sep 19.
• [4] TTBK2 kinase substrate specificity and the impact of spinocerebellar-ataxia-causing mutations on expression, activity, localization and development.Biochem J. 2011 Jul 1;437(1):157-67. doi: 10.1042/BJ20110276.
• [5] PRKX, TTBK2 and RSK4 expression causes Sunitinib resistance in kidney carcinoma- and melanoma-cell lines.Int J Cancer. 2012 Jul 15;131(2):E45-55. doi: 10.1002/ijc.26486. Epub 2012 Feb 28.
• [6] Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11. Nat Genet. 2007 Dec;39(12):1434-6. doi: 10.1038/ng.2007.43. Epub 2007 Nov 25.
• [7] The tau tubulin kinases TTBK1/2 promote accumulation of pathological TDP-43.PLoS Genet. 2014 Dec 4;10(12):e1004803. doi: 10.1371/journal.pgen.1004803. eCollection 2014 Dec.
• [8] Pathological phosphorylation of tau and TDP-43 by TTBK1 and TTBK2 drives neurodegeneration.Mol Neurodegener. 2018 Feb 6;13(1):7. doi: 10.1186/s13024-018-0237-9.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] Epigenetic silencing of novel tumor suppressors in malignant melanoma. Cancer Res. 2006 Dec 1;66(23):11187-93. doi: 10.1158/0008-5472.CAN-06-1274.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [15] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [16] 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.
• [17] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [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.