Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRGEG3Z)

• DOT Name: Kelch-like protein 9 (KLHL9)
• Gene Name: KLHL9
• Related Disease:
  Nemaline myopathy
  Neoplasm
  Acute myelogenous leukaemia
  Tourette syndrome
• UniProt ID: KLHL9_HUMAN
• Pfam ID: PF07707 ; PF00651 ; PF01344
• Sequence:
  MKVSLGNGEMGVSAHLQPCKAGTTRFFTSNTHSSVVLQGFDQLRIEGLLCDVTLVPGDGD
  EIFPVHRAMMASASDYFKAMFTGGMKEQDLMCIKLHGVNKVGLKKIIDFIYTAKLSLNMD
  NLQDTLEAASFLQILPVLDFCKVFLISGVSLDNCVEVGRIANTYNLIEVDKYVNNFILKN
  FPALLSTGEFLKLPFERLAFVLSSNSLKHCTELELFKAACRWLRLEDPRMDYAAKLMKNI
  RFPLMTPQDLINYVQTVDFMRTDNTCVNLLLEASNYQMMPYMQPVMQSDRTAIRSDSTHL
  VTLGGVLRQQLVVSKELRMYDERAQEWRSLAPMDAPRYQHGIAVIGNFLYVVGGQSNYDT
  KGKTAVDTVFRFDPRYNKWMQVASLNEKRTFFHLSALKGHLYAVGGRSAAGELATVECYN
  PRMNEWSYVAKMSEPHYGHAGTVYGGLMYISGGITHDTFQNELMCFDPDTDKWMQKAPMT
  TVRGLHCMCTVGDKLYVIGGNHFRGTSDYDDVLSCEYYSPTLDQWTPIAAMLRGQSDVGV
  AVFENKIYVVGGYSWNNRCMVEIVQKYDPEKDEWHKVFDLPESLGGIRACTLTVFPPEEN
  PGSPSRESPLSAPSDHS
• Function: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex required for mitotic progression and cytokinesis. The BCR(KLHL9-KLHL13) E3 ubiquitin ligase complex mediates the ubiquitination of AURKB and controls the dynamic behavior of AURKB on mitotic chromosomes and thereby coordinates faithful mitotic progression and completion of cytokinesis.
• KEGG Pathway: Ubiquitin mediated proteolysis (hsa04120)
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nemaline myopathy	DIS5IYLY	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[3]
Tourette syndrome	DISX9D54	No Known	Unknown	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Kelch-like protein 9 (KLHL9) affects the response to substance of Fluorouracil.	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Kelch-like protein 9 (KLHL9).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Kelch-like protein 9 (KLHL9).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Kelch-like protein 9 (KLHL9).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Kelch-like protein 9 (KLHL9).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Kelch-like protein 9 (KLHL9).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Kelch-like protein 9 (KLHL9).	[10]

References

• [1] Kelch-like homologue 9 mutation is associated with an early onset autosomal dominant distal myopathy.Brain. 2010 Jul;133(Pt 7):2123-35. doi: 10.1093/brain/awq108. Epub 2010 Jun 16.
• [2] Homozygous deletions at 3p22, 5p14, 6q15, and 9p21 result in aberrant expression of tumor suppressor genes in gastric cancer.Genes Chromosomes Cancer. 2015 Mar;54(3):142-55. doi: 10.1002/gcc.22226. Epub 2014 Dec 17.
• [3] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [4] Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples. Nat Genet. 2017 Apr;49(4):504-510. doi: 10.1038/ng.3789. Epub 2017 Feb 13.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [7] 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.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.