Details of Drug Off-Target (DOT)

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

• DOT Name: Potassium voltage-gated channel subfamily H member 1 (KCNH1)
• Synonyms: Ether-a-go-go potassium channel 1; EAG channel 1; h-eag; hEAG1; Voltage-gated potassium channel subunit Kv10.1
• Gene Name: KCNH1
• Related Disease:
  KCNH1 associated disorder
  Temple-Baraitser syndrome
  Zimmermann-Laband syndrome 1
  Zimmermann-Laband syndrome
• UniProt ID: KCNH1_HUMAN
• PDB ID: 5J7E
• Pfam ID: PF00027 ; PF00520 ; PF13426
• Sequence:
  MTMAGGRRGLVAPQNTFLENIVRRSNDTNFVLGNAQIVDWPIVYSNDGFCKLSGYHRAEV
  MQKSSTCSFMYGELTDKDTIEKVRQTFENYEMNSFEILMYKKNRTPVWFFVKIAPIRNEQ
  DKVVLFLCTFSDITAFKQPIEDDSCKGWGKFARLTRALTSSRGVLQQLAPSVQKGENVHK
  HSRLAEVLQLGSDILPQYKQEAPKTPPHIILHYCVFKTTWDWIILILTFYTAILVPYNVS
  FKTRQNNVAWLVVDSIVDVIFLVDIVLNFHTTFVGPAGEVISDPKLIRMNYLKTWFVIDL
  LSCLPYDVINAFENVDEVSAFMGDPGKIGFADQIPPPLEGRESQGISSLFSSLKVVRLLR
  LGRVARKLDHYIEYGAAVLVLLVCVFGLAAHWMACIWYSIGDYEIFDEDTKTIRNNSWLY
  QLAMDIGTPYQFNGSGSGKWEGGPSKNSVYISSLYFTMTSLTSVGFGNIAPSTDIEKIFA
  VAIMMIGSLLYATIFGNVTTIFQQMYANTNRYHEMLNSVRDFLKLYQVPKGLSERVMDYI
  VSTWSMSRGIDTEKVLQICPKDMRADICVHLNRKVFKEHPAFRLASDGCLRALAMEFQTV
  HCAPGDLIYHAGESVDSLCFVVSGSLEVIQDDEVVAILGKGDVFGDVFWKEATLAQSCAN
  VRALTYCDLHVIKRDALQKVLEFYTAFSHSFSRNLILTYNLRKRIVFRKISDVKREEEER
  MKRKNEAPLILPPDHPVRRLFQRFRQQKEARLAAERGGRDLDDLDVEKGNVLTEHASANH
  SLVKASVVTVRESPATPVSFQAASTSGVPDHAKLQAPGSECLGPKGGGGDCAKRKSWARF
  KDACGKSEDWNKVSKAESMETLPERTKASGEATLKKTDSCDSGITKSDLRLDNVGEARSP
  QDRSPILAEVKHSFYPIPEQTLQATVLEVRHELKEDIKALNAKMTNIEKQLSEILRILTS
  RRSSQSPQELFEISRPQSPESERDIFGAS
• Function: Pore-forming (alpha) subunit of a voltage-gated delayed rectifier potassium channel. Channel properties are modulated by subunit assembly. Mediates IK(NI) current in myoblasts. Involved in the regulation of cell proliferation and differentiation, in particular adipogenic and osteogenic differentiation in bone marrow-derived mesenchymal stem cells (MSCs).
• Tissue Specificity: Highly expressed in brain and in myoblasts at the onset of fusion, but not in other tissues. Detected in HeLa (cervical carcinoma), SH-SY5Y (neuroblastoma) and MCF-7 (epithelial tumor) cells, but not in normal epithelial cells.
• Reactome Pathway: Voltage gated Potassium channels (R-HSA-1296072)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
KCNH1 associated disorder	DISFCDLI	Definitive	Autosomal dominant	[1]
Temple-Baraitser syndrome	DISKRXK4	Strong	Autosomal dominant	[2]
Zimmermann-Laband syndrome 1	DIS3GWZK	Moderate	Autosomal dominant	[3]
Zimmermann-Laband syndrome	DISXXVYH	Supportive	Autosomal recessive	[4]

2 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 Potassium voltage-gated channel subfamily H member 1 (KCNH1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Potassium voltage-gated channel subfamily H member 1 (KCNH1).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Potassium voltage-gated channel subfamily H member 1 (KCNH1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Potassium voltage-gated channel subfamily H member 1 (KCNH1).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Potassium voltage-gated channel subfamily H member 1 (KCNH1).	[8]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Potassium voltage-gated channel subfamily H member 1 (KCNH1).	[7]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Potassium voltage-gated channel subfamily H member 1 (KCNH1).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Potassium voltage-gated channel subfamily H member 1 (KCNH1).	[11]
Astemizole	DM2HN6Q	Withdrawn from market	Astemizole decreases the activity of Potassium voltage-gated channel subfamily H member 1 (KCNH1).	[12]
Desmethylastemizole	DM58XJN	Investigative	Desmethylastemizole decreases the activity of Potassium voltage-gated channel subfamily H member 1 (KCNH1).	[13]

References

• [1] 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.
• [2] Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy. Nat Genet. 2015 Jan;47(1):73-7. doi: 10.1038/ng.3153. Epub 2014 Nov 24.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome. Nat Genet. 2015 Jun;47(6):661-7. doi: 10.1038/ng.3282. Epub 2015 Apr 27.
• [5] 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.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Estrogens and human papilloma virus oncogenes regulate human ether--go-go-1 potassium channel expression. Cancer Res. 2009 Apr 15;69(8):3300-7. doi: 10.1158/0008-5472.CAN-08-2036. Epub 2009 Apr 7.
• [8] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [9] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [10] 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.
• [11] 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.
• [12] Functional and molecular identification of intermediate-conductance Ca(2+)-activated K(+) channels in breast cancer cells: association with cell cycle progression. Am J Physiol Cell Physiol. 2004 Jul;287(1):C125-34. doi: 10.1152/ajpcell.00488.2003. Epub 2004 Feb 25.
• [13] A clinical drug library screen identifies astemizole as an antimalarial agent. Nat Chem Biol. 2006 Aug;2(8):415-6. doi: 10.1038/nchembio806. Epub 2006 Jul 2.