Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBV52DR)

• DOT Name: Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1)
• Synonyms: SMC hinge domain-containing protein 1; EC 3.6.1.-
• Gene Name: SMCHD1
• Related Disease:
  Arhinia, choanal atresia, and microphthalmia
  Muscular dystrophy
  Adult lymphoma
  Anosmia
  Cryptorchidism
  Haematological malignancy
  Immunodeficiency
  leukaemia
  Leukemia
  Lymphoma
  Myopathy
  Neoplasm
  Pediatric lymphoma
  facioscapulohumeral muscular dystrophy
  Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome
• UniProt ID: SMHD1_HUMAN
• PDB ID: 6MW7
• EC Number: 3.6.1.-
• Pfam ID: PF13589 ; PF06470
• Sequence:
  MAAADGGGPGGASVGTEEDGGGVGHRTVYLFDRREKESELGDRPLQVGERSDYAGFRACV
  CQTLGISPEEKFVITTTSRKEITCDNFDETVKDGVTLYLLQSVNQLLLTATKERIDFLPH
  YDTLVKSGMYEYYASEGQNPLPFALAELIDNSLSATSRNIGVRRIQIKLLFDETQGKPAV
  AVIDNGRGMTSKQLNNWAVYRLSKFTRQGDFESDHSGYVRPVPVPRSLNSDISYFGVGGK
  QAVFFVGQSARMISKPADSQDVHELVLSKEDFEKKEKNKEAIYSGYIRNRKPSDSVHITN
  DDERFLHHLIIEEKEKDSFTAVVITGVQPEHIQYLKNYFHLWTRQLAHIYHYYIHGPKGN
  EIRTSKEVEPFNNIDIEISMFEKGKVPKIVNLREIQDDMQTLYVNTAADSFEFKAHVEGD
  GVVEGIIRYHPFLYDRETYPDDPCFPSKLKDEDDEDDCFILEKAARGKRPIFECFWNGRL
  IPYTSVEDFDWCTPPKKRGLAPIECYNRISGALFTNDKFQVSTNKLTFMDLELKLKDKNT
  LFTRILNGQEQRMKIDREFALWLKDCHEKYDKQIKFTLFKGVITRPDLPSKKQGPWATYA
  AIEWDGKIYKAGQLVKTIKTLPLFYGSIVRFFLYGDHDGEVYATGGEVQIAMEPQALYDE
  VRTVPIAKLDRTVAEKAVKKYVEDEMARLPDRLSVTWPEGDELLPNEVRPAGTPIGALRI
  EILNKKGEAMQKLPGTSHGGSKKLLVELKVILHSSSGNKEIISHISQHGGKWPYWFKKME
  NIQKLGNYTLKLQVVLNESNADTYAGRPLPSKAIKFSVKEGKPEKFSFGLLDLPFRVGVP
  FNIPLEFQDEFGHTSQLVTDIQPVLEASGLSLHYEEITKGPNCVIRGVTAKGPVNSCQGK
  NYNLKVTLPGLKEDSQILKIRLLPGHPRRLKVKPDSEILVIENGTAFPFQVEVLDESDNI
  TAQPKLIVHCKFSGAPNLPVYVVDCSSSGTSILTGSAIQVQNIKKDQTLKARIEIPSCKD
  VAPVEKTIKLLPSSHVARLQIFSVEGQKAIQIKHQDEVNWIAGDIMHNLIFQMYDEGERE
  INITSALAEKIKVNWTPEINKEHLLQGLLPDVQVPTSVKDMRYCQVSFQDDHVSLESAFT
  VRPLPDEPKHLKCEMKGGKTVQMGQELQGEVVIIITDQYGNQIQAFSPSSLSSLSIAGVG
  LDSSNLKTTFQENTQSISVRGIKFIPGPPGNKDLCFTWREFSDFIRVQLISGPPAKLLLI
  DWPELKESIPVINGRDLQNPIIVQLCDQWDNPAPVQHVKISLTKASNLKLMPSNQQHKTD
  EKGRANLGVFSVFAPRGEHTLQVKAIYNKSIIEGPIIKLMILPDPEKPVRLNVKYDKDAS
  FLAGGLFTDFMISVISEDDSIIKNINPARISMKMWKLSTSGNRPPANAETFSCNKIKDND
  KEDGCFYFRDKVIPNKVGTYCIQFGFMMDKTNILNSEQVIVEVLPNQPVKLVPKIKPPTP
  AVSNVRSVASRTLVRDLHLSITDDYDNHTGIDLVGTIIATIKGSNEEDTDTPLFIGKVRT
  LEFPFVNGSAEIMSLVLAESSPGRDSTEYFIVFEPRLPLLSRTLEPYILPFMFYNDVKKQ
  QQMAALTKEKDQLSQSIVMYKSLFEASQQLLNEMKCQVEEARLKEAQLRNELKIHNIDIP
  TTQQVPHIEALLKRKLSEQEELKKKPRRSCTLPNYTKGSGDVLGKIAHLAQIEDDRAAMV
  ISWHLASDMDCVVTLTTDAARRIYDETQGRQQVLPLDSIYKKTLPDWKRSLPHFRNGKLY
  FKPIGDPVFARDLLTFPDNVEHCETVFGMLLGDTIILDNLDAANHYRKEVVKITHCPTLL
  TRDGDRIRSNGKFGGLQNKAPPMDKLRGMVFGAPVPKQCLILGEQIDLLQQYRSAVCKLD
  SVNKDLNSQLEYLRTPDMRKKKQELDEHEKNLKLIEEKLGMTPIRKCNDSLRHSPKVETT
  DCPVPPKRMRREATRQNRIITKTDV
• Function: Non-canonical member of the structural maintenance of chromosomes (SMC) protein family that plays a key role in epigenetic silencing by regulating chromatin architecture. Promotes heterochromatin formation in both autosomes and chromosome X, probably by mediating the merge of chromatin compartments. Plays a key role in chromosome X inactivation in females by promoting the spreading of heterochromatin. Recruited to inactivated chromosome X by Xist RNA and acts by mediating the merge of chromatin compartments: promotes random chromatin interactions that span the boundaries of existing structures, leading to create a compartment-less architecture typical of inactivated chromosome X. Required to facilitate Xist RNA spreading. Also required for silencing of a subset of clustered autosomal loci in somatic cells, such as the DUX4 locus. Has ATPase activity; may participate in structural manipulation of chromatin in an ATP-dependent manner as part of its role in gene expression regulation. Also plays a role in DNA repair: localizes to sites of DNA double-strand breaks in response to DNA damage to promote the repair of DNA double-strand breaks. Acts by promoting non-homologous end joining (NHEJ) and inhibiting homologous recombination (HR) repair.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arhinia, choanal atresia, and microphthalmia	DIS7HTFU	Definitive	Autosomal dominant	[1]
Muscular dystrophy	DISJD6P7	Definitive	Biomarker	[2]
Adult lymphoma	DISK8IZR	Strong	Altered Expression	[3]
Anosmia	DISNRJVL	Strong	CausalMutation	[4]
Cryptorchidism	DISYUD2P	Strong	CausalMutation	[4]
Haematological malignancy	DISCDP7W	Strong	Biomarker	[3]
Immunodeficiency	DIS093I0	Strong	Biomarker	[3]
leukaemia	DISS7D1V	Strong	Altered Expression	[3]
Leukemia	DISNAKFL	Strong	Altered Expression	[3]
Lymphoma	DISN6V4S	Strong	Altered Expression	[3]
Myopathy	DISOWG27	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Pediatric lymphoma	DIS51BK2	Strong	Altered Expression	[3]
facioscapulohumeral muscular dystrophy	DISSE0H0	Supportive	Autosomal dominant	[6]
Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome	DISPHHJJ	Supportive	Autosomal dominant	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1).	[18]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1).	[12]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1).	[13]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1).	[14]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1).	[15]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1).	[16]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1).	[20]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1).	[21]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Structural maintenance of chromosomes flexible hinge domain-containing protein 1 (SMCHD1).	[22]

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] A New Role for SMCHD1 in Life's Master Switch and Beyond.Trends Genet. 2019 Dec;35(12):948-955. doi: 10.1016/j.tig.2019.10.001. Epub 2019 Oct 25.
• [3] Epigenetic regulator Smchd1 functions as a tumor suppressor.Cancer Res. 2013 Mar 1;73(5):1591-9. doi: 10.1158/0008-5472.CAN-12-3019. Epub 2012 Dec 26.
• [4] SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome. Nat Genet. 2017 Feb;49(2):238-248. doi: 10.1038/ng.3743. Epub 2017 Jan 9.
• [5] Identification of two novel SMCHD1 sequence variants in families with FSHD-like muscular dystrophy.Eur J Hum Genet. 2015 Jan;23(1):67-71. doi: 10.1038/ejhg.2014.58. Epub 2014 Apr 23.
• [6] Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet. 2012 Dec;44(12):1370-4. doi: 10.1038/ng.2454. Epub 2012 Nov 11.
• [7] De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development. Nat Genet. 2017 Feb;49(2):249-255. doi: 10.1038/ng.3765. Epub 2017 Jan 9.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [17] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.