Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6EGR42)

• DOT Name: BTB/POZ domain-containing protein KCTD3 (KCTD3)
• Synonyms: Renal carcinoma antigen NY-REN-45
• Gene Name: KCTD3
• UniProt ID: KCTD3_HUMAN
• Pfam ID: PF02214
• Sequence:
  MAGGHCGSFPAAAAGSGEIVQLNVGGTRFSTSRQTLMWIPDSFFSSLLSGRISTLRDETG
  AIFIDRDPAAFAPILNFLRTKELDLRGVSINVLRHEAEFYGITPLVRRLLLCEELERSSC
  GSVLFHGYLPPPGIPSRKINNTVRSADSRNGLNSTEGEARGNGTQPVLSGTGEETVRLGF
  PVDPRKVLIVAGHHNWIVAAYAHFAVCYRIKESSGWQQVFTSPYLDWTIERVALNAKVVG
  GPHGDKDKMVAVASESSIILWSVQDGGSGSEIGVFSLGVPVDALFFIGNQLVATSHTGKV
  GVWNAVTQHWQVQDVVPITSYDTAGSFLLLGCNNGSIYYIDMQKFPLRMKDNDLLVTELY
  HDPSNDAITALSVYLTPKTSVSGNWIEIAYGTSSGAVRVIVQHPETVGSGPQLFQTFTVH
  RSPVTKIMLSEKHLVSVCADNNHVRTWTVTRFRGMISTQPGSTPLASFKILSLEETESHG
  SYSSGNDIGPFGERDDQQVFIQKVVPITNKLFVRLSSTGKRICEIQAVDCTTISSFTVRE
  CEGSSRMGSRPRRYLFTGHTNGSIQMWDLTTAMDMVNKSEDKDVGGPTEEELLKLLDQCD
  LSTSRCATPNISPATSVVQHSHLRESNSSLQLQHHDTTHEAATYGSMRPYRESPLLARAR
  RTESFHSYRDFQTINLNRNVERAVPENGNLGPIQAEVKGATGECNISERKSPGVEIKSLR
  ELDSGLEVHKIAEGFSESKKRSSEDENENKIEFRKKGGFEGGGFLGRKKVPYLASSPSTS
  DGGTDSPGTASPSPTKTTPSPRHKKSDSSGQEYSL
• Function: Accessory subunit of potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) up-regulating its cell-surface expression and current density without affecting its voltage dependence and kinetics.
• Tissue Specificity: Broadly expressed in normal tissues.
• Reactome Pathway: CDC42 GTPase cycle (R-HSA-9013148)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	BTB/POZ domain-containing protein KCTD3 (KCTD3) affects the response to substance of Topotecan.	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of BTB/POZ domain-containing protein KCTD3 (KCTD3).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of BTB/POZ domain-containing protein KCTD3 (KCTD3).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of BTB/POZ domain-containing protein KCTD3 (KCTD3).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of BTB/POZ domain-containing protein KCTD3 (KCTD3).	[4]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of BTB/POZ domain-containing protein KCTD3 (KCTD3).	[5]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of BTB/POZ domain-containing protein KCTD3 (KCTD3).	[6]
Fenretinide	DMRD5SP	Phase 3	Fenretinide decreases the expression of BTB/POZ domain-containing protein KCTD3 (KCTD3).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of BTB/POZ domain-containing protein KCTD3 (KCTD3).	[8]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of BTB/POZ domain-containing protein KCTD3 (KCTD3).	[10]

2 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 BTB/POZ domain-containing protein KCTD3 (KCTD3).	[9]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of BTB/POZ domain-containing protein KCTD3 (KCTD3).	[9]

References

• [1] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [2] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [6] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [7] Regulation of lipocalin-2 gene by the cancer chemopreventive retinoid 4-HPR. Int J Cancer. 2006 Oct 1;119(7):1599-606.
• [8] 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.
• [9] 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.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [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.