Details of Drug Off-Target (DOT)

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

• DOT Name: Histone acetyltransferase KAT6B (KAT6B)
• Synonyms: EC 2.3.1.48; Histone acetyltransferase MOZ2; MOZ, YBF2/SAS3, SAS2 and TIP60 protein 4; MYST-4; Monocytic leukemia zinc finger protein-related factor
• Gene Name: KAT6B
• Related Disease:
  Blepharophimosis - intellectual disability syndrome, SBBYS type
  Genitopatellar syndrome
  KAT6B-related multiple congenital anomalies syndrome
  RASopathy
• UniProt ID: KAT6B_HUMAN
• PDB ID: 5U2J; 6OIE; 8E4V
• EC Number: 2.3.1.48
• Pfam ID: PF01853 ; PF00628 ; PF21524 ; PF17772
• Sequence:
  MVKLANPLYTEWILEAIQKIKKQKQRPSEERICHAVSTSHGLDKKTVSEQLELSVQDGSV
  LKVTNKGLASYKDPDNPGRFSSVKPGTFPKSAKGSRGSCNDLRNVDWNKLLRRAIEGLEE
  PNGSSLKNIEKYLRSQSDLTSTTNNPAFQQRLRLGAKRAVNNGRLLKDGPQYRVNYGSLD
  GKGAPQYPSAFPSSLPPVSLLPHEKDQPRADPIPICSFCLGTKESNREKKPEELLSCADC
  GSSGHPSCLKFCPELTTNVKALRWQCIECKTCSACRVQGRNADNMLFCDSCDRGFHMECC
  DPPLSRMPKGMWICQVCRPKKKGRKLLHEKAAQIKRRYAKPIGRPKNKLKQRLLSVTSDE
  GSMNAFTGRGSPGRGQKTKVCTTPSSGHAASGKDSSSRLAVTDPTRPGATTKITTTSTYI
  SASTLKVNKKTKGLIDGLTKFFTPSPDGRRSRGEIIDFSKHYRPRKKVSQKQSCTSHVLA
  TGTTQKLKPPPSSLPPPTPISGQSPSSQKSSTATSSPSPQSSSSQCSVPSLSSLTTNSQL
  KALFDGLSHIYTTQGQSRKKGHPSYAPPKRMRRKTELSSTAKSKAHFFGKRDIRSRFISH
  SSSSSWGMARGSIFKAIAHFKRTTFLKKHRMLGRLKYKVTPQMGTPSPGKGSLTDGRIKP
  DQDDDTEIKINIKQESADVNVIGNKDVVTEEDLDVFKQAQELSWEKIECESGVEDCGRYP
  SVIEFGKYEIQTWYSSPYPQEYARLPKLYLCEFCLKYMKSKNILLRHSKKCGWFHPPANE
  IYRRKDLSVFEVDGNMSKIYCQNLCLLAKLFLDHKTLYYDVEPFLFYVLTKNDEKGCHLV
  GYFSKEKLCQQKYNVSCIMIMPQHQRQGFGRFLIDFSYLLSRREGQAGSPEKPLSDLGRL
  SYLAYWKSVILEYLYHHHERHISIKAISRATGMCPHDIATTLQHLHMIDKRDGRFVIIRR
  EKLILSHMEKLKTCSRANELDPDSLRWTPILISNAAVSEEEREAEKEAERLMEQASCWEK
  EEQEILSTRANSRQSPAKVQSKNKYLHSPESRPVTGERGQLLELSKESSEEEEEEEDEEE
  EEEEEEEEEDEEEEEEEEEEEEEENIQSSPPRLTKPQSVAIKRKRPFVLKKKRGRKRRRI
  NSSVTTETISETTEVLNEPFDNSDEERPMPQLEPTCEIEVEEDGRKPVLRKAFQHQPGKK
  RQTEEEEGKDNHCFKNADPCRNNMNDDSSNLKEGSKDNPEPLKCKQVWPKGTKRGLSKWR
  QNKERKTGFKLNLYTPPETPMEPDEQVTVEEQKETSEGKTSPSPIRIEEEVKETGEALLP
  QEENRREETCAPVSPNTSPGEKPEDDLIKPEEEEEEEEEEEEEEEEEEGEEEEGGGNVEK
  DPDGAKSQEKEEPEISTEKEDSARLDDHEEEEEEDEEPSHNEDHDADDEDDSHMESAEVE
  KEELPRESFKEVLENQETFLDLNVQPGHSNPEVLMDCGVDLTASCNSEPKELAGDPEAVP
  ESDEEPPPGEQAQKQDQKNSKEVDTEFKEGNPATMEIDSETVQAVQSLTQESSEQDDTFQ
  DCAETQEACRSLQNYTRADQSPQIATTLDDCQQSDHSSPVSSVHSHPGQSVRSVNSPSVP
  ALENSYAQISPDQSAISVPSLQNMETSPMMDVPSVSDHSQQVVDSGFSDLGSIESTTENY
  ENPSSYDSTMGGSICGNGSSQNSCSYSNLTSSSLTQSSCAVTQQMSNISGSCSMLQQTSI
  SSPPTCSVKSPQGCVVERPPSSSQQLAQCSMAANFTPPMQLAEIPETSNANIGLYERMGQ
  SDFGAGHYPQPSATFSLAKLQQLTNTLIDHSLPYSHSAAVTSYANSASLSTPLSNTGLVQ
  LSQSPHSVPGGPQAQATMTPPPNLTPPPMNLPPPLLQRNMAASNIGISHSQRLQTQIASK
  GHISMRTKSASLSPAAATHQSQIYGRSQTVAMQGPARTLTMQRGMNMSVNLMPAPAYNVN
  SVNMNMNTLNAMNGYSMSQPMMNSGYHSNHGYMNQTPQYPMQMQMGMMGTQPYAQQPMQT
  PPHGNMMYTAPGHHGYMNTGMSKQSLNGSYMRR
• Function: Histone acetyltransferase which may be involved in both positive and negative regulation of transcription. Required for RUNX2-dependent transcriptional activation. May be involved in cerebral cortex development. Component of the MOZ/MORF complex which has a histone H3 acetyltransferase activity.
• Tissue Specificity: Ubiquitously expressed, with high levels in heart, pancreas, testis and ovary.
• Reactome Pathway: HATs acetylate histones (R-HSA-3214847)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Blepharophimosis - intellectual disability syndrome, SBBYS type	DISOAC2O	Definitive	Autosomal dominant	[1]
Genitopatellar syndrome	DIS5E2L7	Definitive	Autosomal dominant	[1]
KAT6B-related multiple congenital anomalies syndrome	DISWR677	Definitive	Autosomal dominant	[2]
RASopathy	DISPAV44	Disputed	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Histone acetyltransferase KAT6B (KAT6B).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Histone acetyltransferase KAT6B (KAT6B).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Histone acetyltransferase KAT6B (KAT6B).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Histone acetyltransferase KAT6B (KAT6B).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Histone acetyltransferase KAT6B (KAT6B).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Histone acetyltransferase KAT6B (KAT6B).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Histone acetyltransferase KAT6B (KAT6B).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Histone acetyltransferase KAT6B (KAT6B).	[10]
Marinol	DM70IK5	Approved	Marinol increases the expression of Histone acetyltransferase KAT6B (KAT6B).	[11]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Histone acetyltransferase KAT6B (KAT6B).	[12]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Histone acetyltransferase KAT6B (KAT6B).	[10]
Cidofovir	DMA13GD	Approved	Cidofovir decreases the expression of Histone acetyltransferase KAT6B (KAT6B).	[7]
Ifosfamide	DMCT3I8	Approved	Ifosfamide decreases the expression of Histone acetyltransferase KAT6B (KAT6B).	[7]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil decreases the expression of Histone acetyltransferase KAT6B (KAT6B).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Histone acetyltransferase KAT6B (KAT6B).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Histone acetyltransferase KAT6B (KAT6B).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Histone acetyltransferase KAT6B (KAT6B).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Histone acetyltransferase KAT6B (KAT6B).	[18]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Histone acetyltransferase KAT6B (KAT6B).	[19]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of Histone acetyltransferase KAT6B (KAT6B).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Histone acetyltransferase KAT6B (KAT6B).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Histone acetyltransferase KAT6B (KAT6B).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Histone acetyltransferase KAT6B (KAT6B).	[16]

References

• [1] Further delineation of the KAT6B molecular and phenotypic spectrum. Eur J Hum Genet. 2015 Sep;23(9):1165-70. doi: 10.1038/ejhg.2014.248. Epub 2014 Nov 26.
• [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] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [6] 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.
• [7] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [8] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [9] 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.
• [10] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [11] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [12] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [13] 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.
• [14] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [15] 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.
• [16] 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.
• [17] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [18] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [19] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [20] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.