Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD635WX)

• DOT Name: FAST kinase domain-containing protein 2, mitochondrial (FASTKD2)
• Gene Name: FASTKD2
• Related Disease:
  Advanced cancer
  Matthew-Wood syndrome
  Mitochondrial disease
  Pancreatic cancer
  Pancreatic ductal carcinoma
  Breast cancer
  Breast carcinoma
  Combined oxidative phosphorylation deficiency 44
  Cytochrome-c oxidase deficiency disease
  Dementia
  MELAS syndrome
  Neoplasm
  FASTKD2-related infantile mitochondrial encephalomyopathy
  Mitochondrial encephalomyopathy
  Prostate cancer
  Prostate carcinoma
• UniProt ID: FAKD2_HUMAN
• Pfam ID: PF06743 ; PF08368 ; PF08373
• Sequence:
  MLTTLKPFGSVSVESKMNNKAGSFFWNLRQFSTLVSTSRTMRLCCLGLCKPKIVHSNWNI
  LNNFHNRMQSTDIIRYLFQDAFIFKSDVGFQTKGISTLTALRIERLLYAKRLFFDSKQSL
  VPVDKSDDELKKVNLNHEVSNEDVLTKETKPNRISSRKLSEECNSLSDVLDAFSKAPTFP
  SSNYFTAMWTIAKRLSDDQKRFEKRLMFSHPAFNQLCEHMMREAKIMQYKYLLFSLHAIV
  KLGIPQNTILVQTLLRVTQERINECDEICLSVLSTVLEAMEPCKNVHVLRTGFRILVDQQ
  VWKIEDVFTLQVVMKCIGKDAPIALKRKLEMKALRELDRFSVLNSQHMFEVLAAMNHRSL
  ILLDECSKVVLDNIHGCPLRIMINILQSCKDLQYHNLDLFKGLADYVAATFDIWKFRKVL
  FILILFENLGFRPVGLMDLFMKRIVEDPESLNMKNILSILHTYSSLNHVYKCQNKEQFVE
  VMASALTGYLHTISSENLLDAVYSFCLMNYFPLAPFNQLLQKDIISELLTSDDMKNAYKL
  HTLDTCLKLDDTVYLRDIALSLPQLPRELPSSHTNAKVAEVLSSLLGGEGHFSKDVHLPH
  NYHIDFEIRMDTNRNQVLPLSDVDTTSATDIQRVAVLCVSRSAYCLGSSHPRGFLAMKMR
  HLNAMGFHVILVNNWEMDKLEMEDAVTFLKTKIYSVEALPVAAVNVQSTQ
• Function: Plays an important role in assembly of the mitochondrial large ribosomal subunit. As a component of a functional protein-RNA module, consisting of RCC1L, NGRN, RPUSD3, RPUSD4, TRUB2, FASTKD2 and 16S mitochondrial ribosomal RNA (16S mt-rRNA), controls 16S mt-rRNA abundance and is required for intra-mitochondrial translation. May play a role in mitochondrial apoptosis.
• Tissue Specificity: Expression detected in spleen, thymus, testis, ovary, colon, heart, smooth muscle, kidney, brain, lung, liver and white adipose tissue with highest expression in heart, smooth muscle and thyroid.
• Reactome Pathway: FASTK family proteins regulate processing and stability of mitochondrial RNAs (R-HSA-9837092)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Matthew-Wood syndrome	DISA7HR7	Definitive	Biomarker	[1]
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[2]
Pancreatic cancer	DISJC981	Definitive	Biomarker	[1]
Pancreatic ductal carcinoma	DIS26F9Q	Definitive	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Combined oxidative phosphorylation deficiency 44	DISS59GI	Strong	Autosomal recessive	[4]
Cytochrome-c oxidase deficiency disease	DISK7N3G	Strong	Biomarker	[5]
Dementia	DISXL1WY	Strong	Biomarker	[6]
MELAS syndrome	DIS81Z3S	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
FASTKD2-related infantile mitochondrial encephalomyopathy	DIS4IB4B	Supportive	Autosomal recessive	[4]
Mitochondrial encephalomyopathy	DISA6PTN	Limited	Genetic Variation	[5]
Prostate cancer	DISF190Y	Limited	Biomarker	[7]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of FAST kinase domain-containing protein 2, mitochondrial (FASTKD2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of FAST kinase domain-containing protein 2, mitochondrial (FASTKD2).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of FAST kinase domain-containing protein 2, mitochondrial (FASTKD2).	[16]

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 FAST kinase domain-containing protein 2, mitochondrial (FASTKD2).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of FAST kinase domain-containing protein 2, mitochondrial (FASTKD2).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of FAST kinase domain-containing protein 2, mitochondrial (FASTKD2).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of FAST kinase domain-containing protein 2, mitochondrial (FASTKD2).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of FAST kinase domain-containing protein 2, mitochondrial (FASTKD2).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of FAST kinase domain-containing protein 2, mitochondrial (FASTKD2).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of FAST kinase domain-containing protein 2, mitochondrial (FASTKD2).	[17]

References

• [1] FASTKD2 promotes cancer cell progression through upregulating Myc expression in pancreatic ductal adenocarcinoma.J Cell Biochem. 2020 Mar;121(3):2458-2466. doi: 10.1002/jcb.29468. Epub 2019 Nov 6.
• [2] 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.
• [3] A novel transcription complex that selectively modulates apoptosis of breast cancer cells through regulation of FASTKD2.Mol Cell Biol. 2011 Jun;31(11):2287-98. doi: 10.1128/MCB.01381-10. Epub 2011 Mar 28.
• [4] FASTKD2 nonsense mutation in an infantile mitochondrial encephalomyopathy associated with cytochrome c oxidase deficiency. Am J Hum Genet. 2008 Sep;83(3):415-23. doi: 10.1016/j.ajhg.2008.08.009. Epub 2008 Sep 4.
• [5] Identification of FASTKD2 compound heterozygous mutations as the underlying cause of autosomal recessive MELAS-like syndrome.Mitochondrion. 2017 Jul;35:54-58. doi: 10.1016/j.mito.2017.05.005. Epub 2017 May 9.
• [6] FASTKD2 is associated with memory and hippocampal structure in older adults.Mol Psychiatry. 2015 Oct;20(10):1197-204. doi: 10.1038/mp.2014.142. Epub 2014 Nov 11.
• [7] Fas Activated Serine-Threonine Kinase Domains 2 (FASTKD2) mediates apoptosis of breast and prostate cancer cells through its novel FAST2 domain.BMC Cancer. 2014 Nov 20;14:852. doi: 10.1186/1471-2407-14-852.
• [8] 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.
• [9] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [10] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [11] 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.
• [12] 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.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.
• [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.
• [16] 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.
• [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.