Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLDF1OX)

• DOT Name: Kelch domain-containing protein 10 (KLHDC10)
• Gene Name: KLHDC10
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast neoplasm
• UniProt ID: KLD10_HUMAN
• Pfam ID: PF01344 ; PF13418 ; PF13854 ; PF13964
• Sequence:
  MSAAQGWDRNRRRGGGAAGAGGGGSGAGGGSGGSGGRGTGQLNRFVQLSGRPHLPGKKKI
  RWDPVRRRFIQSCPIIRIPNRFLRGHRPPPARSGHRCVADNTNLYVFGGYNPDYDESGGP
  DNEDYPLFRELWRYHFATGVWHQMGTDGYMPRELASMSLVLHGNNLLVFGGTGIPFGESN
  GNDVHVCNVKYKRWALLSCRGKKPSRIYGQAMAIINGSLYVFGGTTGYIYSTDLHKLDLN
  TREWTQLKPNNLSCDLPEERYRHEIAHDGQRIYILGGGTSWTAYSLNKIHAYNLETNAWE
  EIATKPHEKIGFPAARRCHSCVQIKNDVFICGGYNGEVILGDIWKLNLQTFQWVKLPATM
  PEPVYFHCAAVTPAGCMYIHGGVVNIHENKRTGSLFKIWLVVPSLLELAWEKLLAAFPNL
  ANLSRTQLLHLGLTQGLIERLK
• Function: Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation. The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms. The CRL2(KLHDC10) complex specifically recognizes proteins with a proline-glycine (Pro-Gly) or an alanine tail (CAT tail) at the C-terminus, leading to their ubiquitination and degradation. The CRL2(KLHDC10) complex is involved in the ribosome-associated quality control (RQC) pathway, which mediates the extraction of incompletely synthesized nascent chains from stalled ribosomes: CRL2(KLHDC10) acts downstream of NEMF and recognizes CAT tails associated with stalled nascent chains, leading to their ubiquitination and degradation. Participates in the oxidative stress-induced cell death through MAP3K5 activation. Inhibits PPP5C phosphatase activity on MAP3K5. Acts as a regulator of necroptosis.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[1]

11 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 Kelch domain-containing protein 10 (KLHDC10).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Kelch domain-containing protein 10 (KLHDC10).	[3]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Kelch domain-containing protein 10 (KLHDC10).	[4]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Kelch domain-containing protein 10 (KLHDC10).	[5]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Kelch domain-containing protein 10 (KLHDC10).	[6]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Kelch domain-containing protein 10 (KLHDC10).	[7]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Kelch domain-containing protein 10 (KLHDC10).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Kelch domain-containing protein 10 (KLHDC10).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Kelch domain-containing protein 10 (KLHDC10).	[9]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Kelch domain-containing protein 10 (KLHDC10).	[10]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Kelch domain-containing protein 10 (KLHDC10).	[12]

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 Kelch domain-containing protein 10 (KLHDC10).	[11]

References

• [1] A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.Nat Genet. 2018 Jul;50(7):968-978. doi: 10.1038/s41588-018-0132-x. Epub 2018 Jun 18.
• [2] 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.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] 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.
• [5] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [6] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [7] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [8] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [9] 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.
• [10] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [11] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [12] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.