Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVOWKQ7)

• DOT Name: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1)
• Synonyms: Brain cyclic nucleotide-gated channel 1; BCNG-1
• Gene Name: HCN1
• Related Disease:
  Developmental and epileptic encephalopathy, 24
  Generalized epilepsy with febrile seizures plus
  Generalized epilepsy with febrile seizures plus, type 10
  Undetermined early-onset epileptic encephalopathy
• UniProt ID: HCN1_HUMAN
• PDB ID: 5U6O; 5U6P; 6UQF; 6UQG
• Pfam ID: PF00027 ; PF00520 ; PF08412
• Sequence:
  MEGGGKPNSSSNSRDDGNSVFPAKASATGAGPAAAEKRLGTPPGGGGAGAKEHGNSVCFK
  VDGGGGGGGGGGGGEEPAGGFEDAEGPRRQYGFMQRQFTSMLQPGVNKFSLRMFGSQKAV
  EKEQERVKTAGFWIIHPYSDFRFYWDLIMLIMMVGNLVIIPVGITFFTEQTTTPWIIFNV
  ASDTVFLLDLIMNFRTGTVNEDSSEIILDPKVIKMNYLKSWFVVDFISSIPVDYIFLIVE
  KGMDSEVYKTARALRIVRFTKILSLLRLLRLSRLIRYIHQWEEIFHMTYDLASAVVRIFN
  LIGMMLLLCHWDGCLQFLVPLLQDFPPDCWVSLNEMVNDSWGKQYSYALFKAMSHMLCIG
  YGAQAPVSMSDLWITMLSMIVGATCYAMFVGHATALIQSLDSSRRQYQEKYKQVEQYMSF
  HKLPADMRQKIHDYYEHRYQGKIFDEENILNELNDPLREEIVNFNCRKLVATMPLFANAD
  PNFVTAMLSKLRFEVFQPGDYIIREGAVGKKMYFIQHGVAGVITKSSKEMKLTDGSYFGE
  ICLLTKGRRTASVRADTYCRLYSLSVDNFNEVLEEYPMMRRAFETVAIDRLDRIGKKNSI
  LLQKFQKDLNTGVFNNQENEILKQIVKHDREMVQAIAPINYPQMTTLNSTSSTTTPTSRM
  RTQSPPVYTATSLSHSNLHSPSPSTQTPQPSAILSPCSYTTAVCSPPVQSPLAARTFHYA
  SPTASQLSLMQQQPQQQVQQSQPPQTQPQQPSPQPQTPGSSTPKNEVHKSTQALHNTNLT
  REVRPLSASQPSLPHEVSTLISRPHPTVGESLASIPQPVTAVPGTGLQAGGRSTVPQRVT
  LFRQMSSGAIPPNRGVPPAPPPPAAALPRESSSVLNTDPDAEKPRFASNL
• Function: Hyperpolarization-activated ion channel exhibiting weak selectivity for potassium over sodium ions. Contributes to the native pacemaker currents in heart (If) and in neurons (Ih). May mediate responses to sour stimuli.
• Tissue Specificity: Detected in brain, in particular in amygdala and hippocampus, while expression in caudate nucleus, corpus callosum, substantia nigra, subthalamic nucleus and thalamus is very low or not detectable. Detected at very low levels in muscle and pancreas.
• KEGG Pathway: GnRH secretion (hsa04929)
• Reactome Pathway: HCN channels (R-HSA-1296061)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental and epileptic encephalopathy, 24	DISQBXTS	Definitive	Autosomal dominant	[1]
Generalized epilepsy with febrile seizures plus	DISJE0UU	Definitive	Autosomal dominant	[2]
Generalized epilepsy with febrile seizures plus, type 10	DIST9Z03	Strong	Autosomal dominant	[3]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[1]

9 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 Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1).	[5]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1).	[6]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1).	[10]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1).	[11]

References

• [1] De novo mutations in HCN1 cause early infantile epileptic encephalopathy. Nat Genet. 2014 Jun;46(6):640-5. doi: 10.1038/ng.2952. Epub 2014 Apr 20.
• [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] HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond. Brain. 2018 Nov 1;141(11):3160-3178. doi: 10.1093/brain/awy263.
• [4] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [5] 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.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [8] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [9] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [10] 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.
• [11] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.