Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNG4E2M)

• DOT Name: Putative Polycomb group protein ASXL2 (ASXL2)
• Synonyms: Additional sex combs-like protein 2
• Gene Name: ASXL2
• Related Disease:
  Syndromic intellectual disability
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Breast carcinoma
  Cardiac disease
  Dilated cardiomyopathy 1A
  Myelodysplastic syndrome
  Neoplasm
  Shashi-Pena syndrome
  Advanced cancer
  Breast cancer
  Intellectual disability
  leukaemia
  Leukemia
  Megalencephaly
  Melanoma
  Prostate cancer
  Prostate carcinoma
  Mesothelioma
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: ASXL2_HUMAN
• Pfam ID: PF13919 ; PF05066 ; PF13922
• Sequence:
  MREKGRRKKGRTWAEAAKTVLEKYPNTPMSHKEILQVIQREGLKEIRSGTSPLACLNAML
  HTNSRGEEGIFYKVPGRMGVYTLKKDVPDGVKELSEGSEESSDGQSDSQSSENSSSSSDG
  GSNKEGKKSRWKRKVSSSSPQSGCPSPTIPAGKVISPSQKHSKKALKQALKQQQQKKQQQ
  QCRPSISISSNQHLSLKTVKAASDSVPAKPATWEGKQSDGQTGSPQNSNSSFSSSVKVEN
  TLLGLGKKSFQRSERLHTRQMKRTKCADIDVETPDSILVNTNLRALINKHTFSVLPGDCQ
  QRLLLLLPEVDRQVGPDGLMKLNGSALNNEFFTSAAQGWKERLSEGEFTPEMQVRIRQEI
  EKEKKVEPWKEQFFESYYGQSSGLSLEDSKKLTASPSDPKVKKTPAEQPKSMPVSEASLI
  RIVPVVSQSECKEEALQMSSPGRKEECESQGEVQPNFSTSSEPLLSSALNTHELSSILPI
  KCPKDEDLLEQKPVTSAEQESEKNHLTTASNYNKSESQESLVTSPSKPKSPGVEKPIVKP
  TAGAGPQETNMKEPLATLVDQSPESLKRKSSLTQEEAPVSWEKRPRVTENRQHQQPFQVS
  PQPFLNRGDRIQVRKVPPLKIPVSRISPMPFHPSQVSPRARFPVSITSPNRTGARTLADI
  KAKAQLVKAQRAAAAAAAAAAAAASVGGTIPGPGPGGGQGPGEGGEGQTARGGSPGSDRV
  SETGKGPTLELAGTGSRGGTRELLPCGPETQPQSETKTTPSQAQPHSVSGAQLQQTPPVP
  PTPAVSGACTSVPSPAHIEKLDNEKLNPTRATATVASVSHPQGPSSCRQEKAPSPTGPAL
  ISGASPVHCAADGTVELKAGPSKNIPNPSASSKTDASVPVAVTPSPLTSLLTTATLEKLP
  VPQVSATTAPAGSAPPSSTLPAASSLKTPGTSLNMNGPTLRPTSSIPANNPLVTQLLQGK
  DVPMEQILPKPLTKVEMKTVPLTAKEERGMGALIATNTTENSTREEVNERQSHPATQQQL
  GKTLQSKQLPQVPRPLQLFSAKELRDSSIDTHQYHEGLSKATQDQILQTLIQRVRRQNLL
  SVVPPSQFNFAHSGFQLEDISTSQRFMLGFAGRRTSKPAMAGHYLLNISTYGRGSESFRR
  THSVNPEDRFCLSSPTEALKMGYTDCKNATGESSSSKEDDTDEESTGDEQESVTVKEEPQ
  VSQSAGKGDTSSGPHSRETLSTSDCLASKNVKAEIPLNEQTTLSKENYLFTRGQTFDEKT
  LARDLIQAAQKQMAHAVRGKAIRSSPELFSSTVLPLPADSPTHQPLLLPPLQTPKLYGSP
  TQIGPSYRGMINVSTSSDMDHNSAVPGSQVSSNVGDVMSFSVTVTTIPASQAMNPSSHGQ
  TIPVQAFSEENSIEGTPSKCYCRLKAMIMCKGCGAFCHDDCIGPSKLCVSCLVVR
• Function: Putative Polycomb group (PcG) protein. PcG proteins act by forming multiprotein complexes, which are required to maintain the transcriptionally repressive state of homeotic genes throughout development. PcG proteins are not required to initiate repression, but to maintain it during later stages of development. They probably act via methylation of histones, rendering chromatin heritably changed in its expressibility. Involved in transcriptional regulation mediated by ligand-bound nuclear hormone receptors, such as peroxisome proliferator-activated receptor gamma (PPARG). Acts as coactivator for PPARG and enhances its adipocyte differentiation-inducing activity; the function seems to involve differential recruitment of acetylated and methylated histone H3.
• KEGG Pathway: Polycomb repressive complex (hsa03083)
• Reactome Pathway: UCH proteinases (R-HSA-5689603)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Syndromic intellectual disability	DISH7SDF	Definitive	Autosomal dominant	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Genetic Variation	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Cardiac disease	DISVO1I5	Strong	Altered Expression	[4]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[4]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Shashi-Pena syndrome	DISDFUZH	Strong	Autosomal dominant	[7]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[8]
Breast cancer	DIS7DPX1	moderate	Biomarker	[3]
Intellectual disability	DISMBNXP	moderate	Biomarker	[7]
leukaemia	DISS7D1V	moderate	Genetic Variation	[9]
Leukemia	DISNAKFL	moderate	Genetic Variation	[9]
Megalencephaly	DISYW5SV	moderate	Biomarker	[7]
Melanoma	DIS1RRCY	moderate	Biomarker	[10]
Prostate cancer	DISF190Y	moderate	Biomarker	[10]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[10]
Mesothelioma	DISKWK9M	Disputed	Altered Expression	[6]
Urinary bladder cancer	DISDV4T7	Limited	Biomarker	[11]
Urinary bladder neoplasm	DIS7HACE	Limited	Biomarker	[11]

8 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 Putative Polycomb group protein ASXL2 (ASXL2).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Putative Polycomb group protein ASXL2 (ASXL2).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Putative Polycomb group protein ASXL2 (ASXL2).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Putative Polycomb group protein ASXL2 (ASXL2).	[15]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Putative Polycomb group protein ASXL2 (ASXL2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Putative Polycomb group protein ASXL2 (ASXL2).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Putative Polycomb group protein ASXL2 (ASXL2).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Putative Polycomb group protein ASXL2 (ASXL2).	[20]

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 Putative Polycomb group protein ASXL2 (ASXL2).	[18]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Putative Polycomb group protein ASXL2 (ASXL2).	[21]

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] Clinical significance of ASXL2 and ZBTB7A mutations and C-terminally truncated RUNX1-RUNX1T1 expression in AML patients with t(8;21) enrolled in the JALSG AML201 study.Ann Hematol. 2019 Jan;98(1):83-91. doi: 10.1007/s00277-018-3492-5. Epub 2018 Sep 24.
• [3] ASXL2 promotes proliferation of breast cancer cells by linking ER to histone methylation.Oncogene. 2016 Jul 14;35(28):3742-52. doi: 10.1038/onc.2015.443. Epub 2015 Dec 7.
• [4] Maintenance of adult cardiac function requires the chromatin factor Asxl2.J Mol Cell Cardiol. 2012 Nov;53(5):734-41. doi: 10.1016/j.yjmcc.2012.08.014. Epub 2012 Aug 27.
• [5] Loss of Asxl2 leads to myeloid malignancies in mice.Nat Commun. 2017 Jun 8;8:15456. doi: 10.1038/ncomms15456.
• [6] Monoubiquitination of ASXLs controls the deubiquitinase activity of the tumor suppressor BAP1.Nat Commun. 2018 Oct 22;9(1):4385. doi: 10.1038/s41467-018-06854-2.
• [7] De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype. Am J Hum Genet. 2016 Oct 6;99(4):991-999. doi: 10.1016/j.ajhg.2016.08.017. Epub 2016 Sep 29.
• [8] Familial and Somatic BAP1 Mutations Inactivate ASXL1/2-Mediated Allosteric Regulation of BAP1 Deubiquitinase by Targeting Multiple Independent Domains.Cancer Res. 2018 Mar 1;78(5):1200-1213. doi: 10.1158/0008-5472.CAN-17-2876. Epub 2017 Dec 28.
• [9] ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia.Nat Commun. 2017 May 18;8:15429. doi: 10.1038/ncomms15429.
• [10] Functional and cancer genomics of ASXL family members.Br J Cancer. 2013 Jul 23;109(2):299-306. doi: 10.1038/bjc.2013.281. Epub 2013 Jun 4.
• [11] Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy.Nat Genet. 2013 Dec;45(12):1464-9. doi: 10.1038/ng.2799. Epub 2013 Oct 13.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [15] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [16] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [17] Genome-wide transcriptional and functional analysis of human T lymphocytes treated with benzo[alpha]pyrene. Int J Mol Sci. 2018 Nov 17;19(11).
• [18] 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.
• [19] 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.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.