Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUT5NLJ)

• DOT Name: Histone-lysine N-methyltransferase ASH1L (ASH1L)
• Synonyms: EC 2.1.1.359; EC 2.1.1.367; ASH1-like protein; huASH1; Absent small and homeotic disks protein 1 homolog; Lysine N-methyltransferase 2H
• Gene Name: ASH1L
• Related Disease:
  Hereditary gingival fibromatosis
  Non-small-cell lung cancer
  Syndromic complex neurodevelopmental disorder
  Advanced cancer
  Autism spectrum disorder
  Autoimmune disease
  Breast carcinoma
  Castration-resistant prostate carcinoma
  Colitis
  Duchenne muscular dystrophy
  Esophageal squamous cell carcinoma
  Intellectual disability
  Intellectual disability, autosomal dominant 40
  Intellectual disability, autosomal dominant 52
  Lewy body dementia
  Liver cancer
  Lung cancer
  Neurodevelopmental disorder
  Pituitary adenoma
  Prostate cancer
  Prostate neoplasm
  Stomach cancer
  Tourette syndrome
  Usher syndrome type 1B
  Carcinoma
  leukaemia
  Leukemia
  Lung carcinoma
  Small-cell lung cancer
  Autosomal dominant non-syndromic intellectual disability
  Attention deficit hyperactivity disorder
  facioscapulohumeral muscular dystrophy
  Neoplasm
  Neuroblastoma
• UniProt ID: ASH1L_HUMAN
• PDB ID: 3MQM; 3OPE; 4YNM; 4YNP; 4YPA; 4YPE; 4YPU; 6AGO; 6INE; 6WZW; 6X0P; 7Y0I
• EC Number: 2.1.1.359; 2.1.1.367
• Pfam ID: PF17907 ; PF01426 ; PF00439 ; PF20826 ; PF00856
• Sequence:
  MDPRNTAMLGLGSDSEGFSRKSPSAISTGTLVSKREVELEKNTKEEEDLRKRNRERNIEA
  GKDDGLTDAQQQFSVKETNFSEGNLKLKIGLQAKRTKKPPKNLENYVCRPAIKTTIKHPR
  KALKSGKMTDEKNEHCPSKRDPSKLYKKADDVAAIECQSEEVIRLHSQGENNPLSKKLSP
  VHSEMADYINATPSTLLGSRDPDLKDRALLNGGTSVTEKLAQLIATCPPSKSSKTKPKKL
  GTGTTAGLVSKDLIRKAGVGSVAGIIHKDLIKKPTISTAVGLVTKDPGKKPVFNAAVGLV
  NKDSVKKLGTGTTAVFINKNLGKKPGTITTVGLLSKDSGKKLGIGIVPGLVHKESGKKLG
  LGTVVGLVNKDLGKKLGSTVGLVAKDCAKKIVASSAMGLVNKDIGKKLMSCPLAGLISKD
  AINLKAEALLPTQEPLKASCSTNINNQESQELSESLKDSATSKTFEKNVVRQNKESILEK
  FSVRKEIINLEKEMFNEGTCIQQDSFSSSEKGSYETSKHEKQPPVYCTSPDFKMGGASDV
  STAKSPFSAVGESNLPSPSPTVSVNPLTRSPPETSSQLAPNPLLLSSTTELIEEISESVG
  KNQFTSESTHLNVGHRSVGHSISIECKGIDKEVNDSKTTHIDIPRISSSLGKKPSLTSES
  SIHTITPSVVNFTSLFSNKPFLKLGAVSASDKHCQVAESLSTSLQSKPLKKRKGRKPRWT
  KVVARSTCRSPKGLELERSELFKNVSCSSLSNSNSEPAKFMKNIGPPSFVDHDFLKRRLP
  KLSKSTAPSLALLADSEKPSHKSFATHKLSSSMCVSSDLLSDIYKPKRGRPKSKEMPQLE
  GPPKRTLKIPASKVFSLQSKEEQEPPILQPEIEIPSFKQGLSVSPFPKKRGRPKRQMRSP
  VKMKPPVLSVAPFVATESPSKLESESDNHRSSSDFFESEDQLQDPDDLDDSHRPSVCSMS
  DLEMEPDKKITKRNNGQLMKTIIRKINKMKTLKRKKLLNQILSSSVESSNKGKVQSKLHN
  TVSSLAATFGSKLGQQINVSKKGTIYIGKRRGRKPKTVLNGILSGSPTSLAVLEQTAQQA
  AGSALGQILPPLLPSSASSSEILPSPICSQSSGTSGGQSPVSSDAGFVEPSSVPYLHLHS
  RQGSMIQTLAMKKASKGRRRLSPPTLLPNSPSHLSELTSLKEATPSPISESHSDETIPSD
  SGIGTDNNSTSDRAEKFCGQKKRRHSFEHVSLIPPETSTVLSSLKEKHKHKCKRRNHDYL
  SYDKMKRQKRKRKKKYPQLRNRQDPDFIAELEELISRLSEIRITHRSHHFIPRDLLPTIF
  RINFNSFYTHPSFPLDPLHYIRKPDLKKKRGRPPKMREAMAEMPFMHSLSFPLSSTGFYP
  SYGMPYSPSPLTAAPIGLGYYGRYPPTLYPPPPSPSFTTPLPPPSYMHAGHLLLNPAKYH
  KKKHKLLRQEAFLTTSRTPLLSMSTYPSVPPEMAYGWMVEHKHRHRHKHREHRSSEQPQV
  SMDTGSSRSVLESLKRYRFGKDAVGERYKHKEKHRCHMSCPHLSPSKSLINREEQWVHRE
  PSESSPLALGLQTPLQIDCSESSPSLSLGGFTPNSEPASSDEHTNLFTSAIGSCRVSNPN
  SSGRKKLTDSPGLFSAQDTSLNRLHRKESLPSNERAVQTLAGSQPTSDKPSQRPSESTNC
  SPTRKRSSSESTSSTVNGVPSRSPRLVASGDDSVDSLLQRMVQNEDQEPMEKSIDAVIAT
  ASAPPSSSPGRSHSKDRTLGKPDSLLVPAVTSDSCNNSISLLSEKLTSSCSPHHIKRSVV
  EAMQRQARKMCNYDKILATKKNLDHVNKILKAKKLQRQARTGNNFVKRRPGRPRKCPLQA
  VVSMQAFQAAQFVNPELNRDEEGAALHLSPDTVTDVIEAVVQSVNLNPEHKKGLKRKGWL
  LEEQTRKKQKPLPEEEEQENNKSFNEAPVEIPSPSETPAKPSEPESTLQPVLSLIPREKK
  PPRPPKKKYQKAGLYSDVYKTTDPKSRLIQLKKEKLEYTPGEHEYGLFPAPIHVVFFVSG
  KYLRQKRIDFQLPYDILWQWKHNQLYKKPDVPLYKKIRSNVYVDVKPLSGYEATTCNCKK
  PDDDTRKGCVDDCLNRMIFAECSPNTCPCGEQCCNQRIQRHEWVQCLERFRAEEKGWGIR
  TKEPLKAGQFIIEYLGEVVSEQEFRNRMIEQYHNHSDHYCLNLDSGMVIDSYRMGNEARF
  INHSCDPNCEMQKWSVNGVYRIGLYALKDMPAGTELTYDYNFHSFNVEKQQLCKCGFEKC
  RGIIGGKSQRVNGLTSSKNSQPMATHKKSGRSKEKRKSKHKLKKRRGHLSEEPSENINTP
  TRLTPQLQMKPMSNRERNFVLKHHVFLVRNWEKIRQKQEEVKHTSDNIHSASLYTRWNGI
  CRDDGNIKSDVFMTQFSALQTARSVRTRRLAAAEENIEVARAARLAQIFKEICDGIISYK
  DSSRQALAAPLLNLPPKKKNADYYEKISDPLDLITIEKQILTGYYKTVEAFDADMLKVFR
  NAEKYYGRKSPVGRDVCRLRKAYYNARHEASAQIDEIVGETASEADSSETSVSEKENGHE
  KDDDVIRCICGLYKDEGLMIQCDKCMVWQHCDCMGVNSDVEHYLCEQCDPRPVDREVPMI
  PRPHYAQPGCVYFICLLRDDLLLRQGDCVYLMRDSRRTPDGHPVRQSYRLLSHINRDKLD
  IFRIEKLWKNEKEERFAFGHHYFRPHETHHSPSRRFYHNELFRVPLYEIIPLEAVVGTCC
  VLDLYTYCKGRPKGVKEQDVYICDYRLDKSAHLFYKIHRNRYPVCTKPYAFDHFPKKLTP
  KKDFSPHYVPDNYKRNGGRSSWKSERSKPPLKDLGQEDDALPLIEEVLASQEQAANEIPS
  LEEPEREGATANVSEGEKKTEESSQEPQSTCTPEERRHNQRERLNQILLNLLEKIPGKNA
  IDVTYLLEEGSGRKLRRRTLFIPENSFRK
• Function: Histone methyltransferase specifically trimethylating 'Lys-36' of histone H3 forming H3K36me3. Also monomethylates 'Lys-9' of histone H3 (H3K9me1) in vitro. The physiological significance of the H3K9me1 activity is unclear.
• Tissue Specificity: Widely expressed, with highest level in brain, heart and kidney.
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Metabolic pathways (hsa01100)
• Reactome Pathway: PKMTs methylate histone lysines (R-HSA-3214841)
• BioCyc Pathway: MetaCyc:HS04019-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary gingival fibromatosis	DISN1ML3	Definitive	Altered Expression	[1]
Non-small-cell lung cancer	DIS5Y6R9	Definitive	Genetic Variation	[2]
Syndromic complex neurodevelopmental disorder	DISJ2RXI	Definitive	Autosomal dominant	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[5]
Autoimmune disease	DISORMTM	Strong	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[7]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Biomarker	[8]
Colitis	DISAF7DD	Strong	Biomarker	[6]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Altered Expression	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[9]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[10]
Intellectual disability, autosomal dominant 40	DISAI0IH	Strong	Autosomal dominant	[11]
Intellectual disability, autosomal dominant 52	DISJKFGG	Strong	Autosomal dominant	[12]
Lewy body dementia	DISAE66J	Strong	Genetic Variation	[13]
Liver cancer	DISDE4BI	Strong	Biomarker	[14]
Lung cancer	DISCM4YA	Strong	Biomarker	[15]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[10]
Pituitary adenoma	DISJ5R1X	Strong	Biomarker	[16]
Prostate cancer	DISF190Y	Strong	Biomarker	[17]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[17]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[18]
Tourette syndrome	DISX9D54	Strong	Biomarker	[19]
Usher syndrome type 1B	DISWTUHR	Strong	Genetic Variation	[20]
Carcinoma	DISH9F1N	moderate	Altered Expression	[21]
leukaemia	DISS7D1V	moderate	Biomarker	[22]
Leukemia	DISNAKFL	moderate	Biomarker	[22]
Lung carcinoma	DISTR26C	moderate	Biomarker	[15]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[23]
Autosomal dominant non-syndromic intellectual disability	DISD6L06	Supportive	Autosomal dominant	[24]
Attention deficit hyperactivity disorder	DISL8MX9	Limited	Genetic Variation	[10]
facioscapulohumeral muscular dystrophy	DISSE0H0	Limited	Biomarker	[25]
Neoplasm	DISZKGEW	Limited	Altered Expression	[16]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[26]

3 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 Histone-lysine N-methyltransferase ASH1L (ASH1L).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Histone-lysine N-methyltransferase ASH1L (ASH1L).	[31]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Histone-lysine N-methyltransferase ASH1L (ASH1L).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Histone-lysine N-methyltransferase ASH1L (ASH1L).	[28]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Histone-lysine N-methyltransferase ASH1L (ASH1L).	[29]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Histone-lysine N-methyltransferase ASH1L (ASH1L).	[30]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Histone-lysine N-methyltransferase ASH1L (ASH1L).	[32]

References

• [1] Mutant MMP-9 and HGF gene transfer enhance resolution of CCl4-induced liver fibrosis in rats: role of ASH1 and EZH2 methyltransferases repression.PLoS One. 2014 Nov 7;9(11):e112384. doi: 10.1371/journal.pone.0112384. eCollection 2014.
• [2] Multigene real-time PCR detection of circulating tumor cells in peripheral blood of lung cancer patients.Anticancer Res. 2006 Mar-Apr;26(2B):1567-75.
• [3] 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.
• [4] The Trithorax protein Ash1L promotes myoblast fusion by activating Cdon expression.Nat Commun. 2018 Nov 28;9(1):5026. doi: 10.1038/s41467-018-07313-8.
• [5] Novel MCA/ID syndrome with ASH1L mutation.Am J Med Genet A. 2017 Jun;173(6):1644-1648. doi: 10.1002/ajmg.a.38193. Epub 2017 Apr 10.
• [6] Ash1l and lnc-Smad3 coordinate Smad3 locus accessibility to modulate iTreg polarization and T cell autoimmunity.Nat Commun. 2017 Jun 9;8:15818. doi: 10.1038/ncomms15818.
• [7] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [8] Integrated Analysis of Genetic Abnormalities of the Histone Lysine Methyltransferases in Prostate Cancer.Med Sci Monit. 2019 Jan 7;25:193-239. doi: 10.12659/MSM.912294.
• [9] Identification of genomic alterations in oesophageal squamous cell cancer.Nature. 2014 May 1;509(7498):91-5. doi: 10.1038/nature13176. Epub 2014 Mar 16.
• [10] De novo loss-of-function variants of ASH1L are associated with an emergent neurodevelopmental disorder.Eur J Med Genet. 2019 Jan;62(1):55-60. doi: 10.1016/j.ejmg.2018.05.003. Epub 2018 May 22.
• [11] Excess of rare, inherited truncating mutations in autism. Nat Genet. 2015 Jun;47(6):582-8. doi: 10.1038/ng.3303. Epub 2015 May 11.
• [12] De novo genic mutations among a Chinese autism spectrum disorder cohort. Nat Commun. 2016 Nov 8;7:13316. doi: 10.1038/ncomms13316.
• [13] GBA and APOE 4 associate with sporadic dementia with Lewy bodies in European genome wide association study.Sci Rep. 2019 May 7;9(1):7013. doi: 10.1038/s41598-019-43458-2.
• [14] Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer.Nat Genet. 2016 May;48(5):500-9. doi: 10.1038/ng.3547. Epub 2016 Apr 11.
• [15] Achaete-scute homologue-1 (ASH1) stimulates migration of lung cancer cells through Cdk5/p35 pathway.Mol Biol Cell. 2012 Aug;23(15):2856-66. doi: 10.1091/mbc.E10-12-1010. Epub 2012 Jun 13.
• [16] Human pituitary tumours express the bHLH transcription factors NeuroD1 and ASH1.J Endocrinol Invest. 2003 Oct;26(10):957-65. doi: 10.1007/BF03348192.
• [17] Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets.Nat Genet. 2018 May;50(5):682-692. doi: 10.1038/s41588-018-0086-z. Epub 2018 Apr 16.
• [18] Identification of new susceptibility loci for gastric non-cardia adenocarcinoma: pooled results from two Chinese genome-wide association studies.Gut. 2017 Apr;66(4):581-587. doi: 10.1136/gutjnl-2015-310612. Epub 2015 Dec 23.
• [19] Mutations in ASH1L confer susceptibility to Tourette syndrome.Mol Psychiatry. 2020 Feb;25(2):476-490. doi: 10.1038/s41380-019-0560-8. Epub 2019 Oct 31.
• [20] Unconventional myosins and the genetics of hearing loss.Am J Med Genet. 1999 Sep 24;89(3):147-57. doi: 10.1002/(sici)1096-8628(19990924)89:3<147::aid-ajmg5>3.0.co;2-6.
• [21] miR-142-3p down-regulation contributes to thyroid follicular tumorigenesis by targeting ASH1L and MLL1.J Clin Endocrinol Metab. 2015 Jan;100(1):E59-69. doi: 10.1210/jc.2014-2280.
• [22] ASH1L Links Histone H3 Lysine 36 Dimethylation to MLL Leukemia.Cancer Discov. 2016 Jul;6(7):770-83. doi: 10.1158/2159-8290.CD-16-0058. Epub 2016 May 6.
• [23] Comparative analysis of TTF-1 binding DNA regions in small-cell lung cancer and non-small-cell lung cancer.Mol Oncol. 2020 Feb;14(2):277-293. doi: 10.1002/1878-0261.12608. Epub 2019 Dec 15.
• [24] Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012 Nov 15;367(20):1921-9. doi: 10.1056/NEJMoa1206524. Epub 2012 Oct 3.
• [25] A long ncRNA links copy number variation to a polycomb/trithorax epigenetic switch in FSHD muscular dystrophy.Cell. 2012 May 11;149(4):819-31. doi: 10.1016/j.cell.2012.03.035. Epub 2012 Apr 26.
• [26] Tat-PTD-modified oncolytic adenovirus driven by the SCG3 promoter and ASH1 enhancer for neuroblastoma therapy.Hum Gene Ther. 2013 Aug;24(8):766-75. doi: 10.1089/hum.2012.132.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Alcohol triggered bile acid disequilibrium by suppressing BSEP to sustain hepatocellular carcinoma progression. Chem Biol Interact. 2022 Apr 1;356:109847. doi: 10.1016/j.cbi.2022.109847. Epub 2022 Feb 9.
• [31] 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.
• [32] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [33] 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.