Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2OF1O8)

• DOT Name: Kelch-like protein 7 (KLHL7)
• Gene Name: KLHL7
• Related Disease:
  PERCHING syndrome
  Advanced cancer
  Bohring-Opitz syndrome
  Breast cancer
  Breast carcinoma
  Buschke-Ollendorff syndrome
  Cold-induced sweating syndrome 1
  Congenital contractures of the limbs and face, hypotonia, and developmental delay
  Retinitis pigmentosa 42
  Small lymphocytic lymphoma
  Chronic obstructive pulmonary disease
  Retinopathy
  Cold-induced sweating syndrome
  Retinitis pigmentosa
  Multiple sclerosis
  Nervous system disease
  Gastric cancer
  Neoplasm
  Stomach cancer
• UniProt ID: KLHL7_HUMAN
• PDB ID: 3II7
• Pfam ID: PF07707 ; PF00651 ; PF01344
• Sequence:
  MAASGVEKSSKKKTEKKLAAREEAKLLAGFMGVMNNMRKQKTLCDVILMVQERKIPAHRV
  VLAAASHFFNLMFTTNMLESKSFEVELKDAEPDIIEQLVEFAYTARISVNSNNVQSLLDA
  ANQYQIEPVKKMCVDFLKEQVDASNCLGISVLAECLDCPELKATADDFIHQHFTEVYKTD
  EFLQLDVKRVTHLLNQDTLTVRAEDQVYDAAVRWLKYDEPNRQPFMVDILAKVRFPLISK
  NFLSKTVQAEPLIQDNPECLKMVISGMRYHLLSPEDREELVDGTRPRRKKHDYRIALFGG
  SQPQSCRYFNPKDYSWTDIRCPFEKRRDAACVFWDNVVYILGGSQLFPIKRMDCYNVVKD
  SWYSKLGPPTPRDSLAACAAEGKIYTSGGSEVGNSALYLFECYDTRTESWHTKPSMLTQR
  CSHGMVEANGLIYVCGGSLGNNVSGRVLNSCEVYDPATETWTELCPMIEARKNHGLVFVK
  DKIFAVGGQNGLGGLDNVEYYDIKLNEWKMVSPMPWKGVTVKCAAVGSIVYVLAGFQGVG
  RLGHILEYNTETDKWVANSKVRAFPVTSCLICVVDTCGANEETLET
• Function: Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex. The BCR(KLHL7) complex acts by mediating ubiquitination and subsequent degradation of substrate proteins. Probably mediates 'Lys-48'-linked ubiquitination.
• Tissue Specificity: Widely expressed, with highest levels in adult and fetal heart, CNS and adult testis.

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
PERCHING syndrome	DISLJHE3	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Bohring-Opitz syndrome	DIS1DZV4	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Buschke-Ollendorff syndrome	DIS9J6VP	Strong	Genetic Variation	[3]
Cold-induced sweating syndrome 1	DISMMSP9	Strong	GermlineCausalMutation	[1]
Congenital contractures of the limbs and face, hypotonia, and developmental delay	DIS1JHCE	Strong	Genetic Variation	[5]
Retinitis pigmentosa 42	DIS5P81S	Strong	Autosomal dominant	[6]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[2]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[7]
Retinopathy	DISB4B0F	moderate	Genetic Variation	[6]
Cold-induced sweating syndrome	DISSVMUD	Supportive	Autosomal recessive	[1]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[8]
Multiple sclerosis	DISB2WZI	Disputed	Biomarker	[9]
Nervous system disease	DISJ7GGT	Disputed	Biomarker	[9]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[2]
Neoplasm	DISZKGEW	Limited	Altered Expression	[2]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Kelch-like protein 7 (KLHL7) affects the response to substance of Fluorouracil.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Kelch-like protein 7 (KLHL7).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Kelch-like protein 7 (KLHL7).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Kelch-like protein 7 (KLHL7).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kelch-like protein 7 (KLHL7).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Kelch-like protein 7 (KLHL7).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Kelch-like protein 7 (KLHL7).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Kelch-like protein 7 (KLHL7).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Kelch-like protein 7 (KLHL7).	[17]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Kelch-like protein 7 (KLHL7).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Kelch-like protein 7 (KLHL7).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Kelch-like protein 7 (KLHL7).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Kelch-like protein 7 (KLHL7).	[21]

References

• [1] Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated with Early-Onset Retinitis Pigmentosa. Am J Hum Genet. 2016 Jul 7;99(1):236-45. doi: 10.1016/j.ajhg.2016.05.026.
• [2] Prognostic value of the cancer oncogene Kelch-like 6 in gastric cancer.Br J Surg. 2017 Dec;104(13):1847-1856. doi: 10.1002/bjs.10628. Epub 2017 Oct 17.
• [3] Two siblings with a novel nonsense variant provide further delineation of the spectrum of recessive KLHL7 diseases.Eur J Med Genet. 2019 Sep;62(9):103551. doi: 10.1016/j.ejmg.2018.10.003. Epub 2018 Oct 6.
• [4] Clinical and biological roles of Kelch-like family member 7 in breast cancer: a marker of poor prognosis.Breast Cancer Res Treat. 2018 Aug;170(3):525-533. doi: 10.1007/s10549-018-4777-z. Epub 2018 Apr 9.
• [5] Crisponi/cold-induced sweating syndrome: Differential diagnosis, pathogenesis and treatment concepts.Clin Genet. 2020 Jan;97(1):209-221. doi: 10.1111/cge.13639. Epub 2019 Sep 16.
• [6] Mutations in a BTB-Kelch protein, KLHL7, cause autosomal-dominant retinitis pigmentosa. Am J Hum Genet. 2009 Jun;84(6):792-800. doi: 10.1016/j.ajhg.2009.05.007.
• [7] A genome-wide association study of chronic obstructive pulmonary disease in Hispanics.Ann Am Thorac Soc. 2015 Mar;12(3):340-8. doi: 10.1513/AnnalsATS.201408-380OC.
• [8] Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [updated 2023 Apr 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [9] Detection of autoantibodies to the BTB-kelch protein KLHL7 in cancer sera.Scand J Immunol. 2006 Sep;64(3):325-35. doi: 10.1111/j.1365-3083.2006.01821.x.
• [10] 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.
• [11] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [12] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [13] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] Quantitative proteomic analysis of HepG2 cells treated with quercetin suggests IQGAP1 involved in quercetin-induced regulation of cell proliferation and migration. OMICS. 2009 Apr;13(2):93-103. doi: 10.1089/omi.2008.0075.
• [17] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [18] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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.