Details of Drug Off-Target (DOT)

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

• DOT Name: Sterile alpha motif domain-containing protein 9-like (SAMD9L)
• Synonyms: SAM domain-containing protein 9-like
• Gene Name: SAMD9L
• Related Disease:
  Ataxia-pancytopenia syndrome
  Advanced cancer
  Cerebellar ataxia
  Hematologic disease
  Hepatitis B virus infection
  Hepatocellular carcinoma
  MIRAGE syndrome
  Myelodysplastic syndrome
  Pancytopenia
  Pathologic nystagmus
  Systemic lupus erythematosus
  Systemic sclerosis
  Spinocerebellar ataxia 49
• UniProt ID: SAM9L_HUMAN
• Sequence:
  MSKQVSLPEMIKDWTKEHVKKWVNEDLKINEQYGQILLSEEVTGLVLQELTEKDLVEMGL
  PWGPALLIKRSYNKLNSKSPESDNHDPGQLDNSKPSKTEHQKNPKHTKKEEENSMSSNID
  YDPREIRDIKQEESILMKENVLDEVANAKHKKKGKLKPEQLTCMPYPFDQFHDSHRYIEH
  YTLQPETGALNLIDPIHEFKALTNTETATEVDIKMKFSNEVFRFASACMNSRTNGTIHFG
  VKDKPHGEIVGVKITSKAAFIDHFNVMIKKYFEESEINEAKKCIREPRFVEVLLQNNTPS
  DRFVIEVDTIPKHSICNDKYFYIQMQICKDKIWKQNQNLSLFVREGASSRDILANSKQRD
  VDFKAFLQNLKSLVASRKEAEEEYGMKAMKKESEGLKLVKLLIGNRDSLDNSYYDWYILV
  TNKCHPNQIKHLDFLKEIKWFAVLEFDPESMINGVVKAYKESRVANLHFPNQYEDKTTNM
  WEKISTLNLYQQPSWIFCNGRSDLKSETYKPLEPHLWQRERASEVRKLILFLTDENIMTR
  GKFLVVFLLLSSVESPGDPLIETFWAFYQALKGMENMLCISVNSHIYQRWKDLLQTRMKM
  EDELTNHSISTLNIELVNSTILKLKSVTRSSRRFLPARGSSSVILEKKKEDVLTALEILC
  ENECTETDIEKDKSKFLEFKKSKEEHFYRGGKVSWWNFYFSSENYSSDFVKRDSYEKLKD
  LIHCWAESPKPIFAKIINLYHHPGCGGTTLAMHVLWDLKKNFRCAVLKNKTTDFAEIAEQ
  VINLVTYRAKSHQDYIPVLLLVDDFEEQENVYFLQNAIHSVLAEKDLRYEKTLVIILNCM
  RSRNPDESAKLADSIALNYQLSSKEQRAFGAKLKEIEKQHKNCENFYSFMIMKSNFDETY
  IENVVRNILKGQDVDSKEAQLISFLALLSSYVTDSTISVSQCEIFLGIIYTSTPWEPESL
  EDKMGTYSTLLIKTEVAEYGRYTGVRIIHPLIALYCLKELERSYHLDKCQIALNILEENL
  FYDSGIGRDKFQHDVQTLLLTRQRKVYGDETDTLFSPLMEALQNKDIEKVLSAGSRRFPQ
  NAFICQALARHFYIKEKDFNTALDWARQAKMKAPKNSYISDTLGQVYKSEIKWWLDGNKN
  CRSITVNDLTHLLEAAEKASRAFKESQRQTDSKNYETENWSPQKSQRRYDMYNTACFLGE
  IEVGLYTIQILQLTPFFHKENELSKKHMVQFLSGKWTIPPDPRNECYLALSKFTSHLKNL
  QSDLKRCFDFFIDYMVLLKMRYTQKEIAEIMLSKKVSRCFRKYTELFCHLDPCLLQSKES
  QLLQEENCRKKLEALRADRFAGLLEYLNPNYKDATTMESIVNEYAFLLQQNSKKPMTNEK
  QNSILANIILSCLKPNSKLIQPLTTLKKQLREVLQFVGLSHQYPGPYFLACLLFWPENQE
  LDQDSKLIEKYVSSLNRSFRGQYKRMCRSKQASTLFYLGKRKGLNSIVHKAKIEQYFDKA
  QNTNSLWHSGDVWKKNEVKDLLRRLTGQAEGKLISVEYGTEEKIKIPVISVYSGPLRSGR
  NIERVSFYLGFSIEGPLAYDIEVI
• Function: May be involved in endosome fusion. Mediates down-regulation of growth factor signaling via internalization of growth factor receptors.
• Tissue Specificity: Widely expressed in adult and fetal tissues. Expressed in the cerebellum . Variable expression in tumors. Down-regulated in breast cancer.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ataxia-pancytopenia syndrome	DISF2733	Definitive	Autosomal dominant	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[3]
Hematologic disease	DIS9XD9A	Strong	Genetic Variation	[3]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
MIRAGE syndrome	DISQS0OS	Strong	Genetic Variation	[3]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[3]
Pancytopenia	DISVKEHV	Strong	Genetic Variation	[3]
Pathologic nystagmus	DIS1QSPO	Strong	Genetic Variation	[5]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[6]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[6]
Spinocerebellar ataxia 49	DISIIN6B	Limited	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Sterile alpha motif domain-containing protein 9-like (SAMD9L).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sterile alpha motif domain-containing protein 9-like (SAMD9L).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sterile alpha motif domain-containing protein 9-like (SAMD9L).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sterile alpha motif domain-containing protein 9-like (SAMD9L).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sterile alpha motif domain-containing protein 9-like (SAMD9L).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Sterile alpha motif domain-containing protein 9-like (SAMD9L).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Sterile alpha motif domain-containing protein 9-like (SAMD9L).	[13]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Sterile alpha motif domain-containing protein 9-like (SAMD9L).	[14]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Sterile alpha motif domain-containing protein 9-like (SAMD9L).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Sterile alpha motif domain-containing protein 9-like (SAMD9L).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Sterile alpha motif domain-containing protein 9-like (SAMD9L).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Sterile alpha motif domain-containing protein 9-like (SAMD9L).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sterile alpha motif domain-containing protein 9-like (SAMD9L).	[16]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes.JCI Insight. 2018 Jul 26;3(14):e121086. doi: 10.1172/jci.insight.121086. eCollection 2018 Jul 26.
• [3] Outcomes of Hematopoietic Cell Transplantation in Patients with Germline SAMD9/SAMD9L Mutations.Biol Blood Marrow Transplant. 2019 Nov;25(11):2186-2196. doi: 10.1016/j.bbmt.2019.07.007. Epub 2019 Jul 12.
• [4] SAMD9L inactivation promotes cell proliferation via facilitating G1-S transition in hepatitis B virus-associated hepatocellular carcinoma.Int J Biol Sci. 2014 Jul 17;10(8):807-16. doi: 10.7150/ijbs.9143. eCollection 2014.
• [5] SAMD9 and SAMD9L in inherited predisposition to ataxia, pancytopenia, and myeloid malignancies.Leukemia. 2018 May;32(5):1106-1115. doi: 10.1038/s41375-018-0074-4. Epub 2018 Feb 25.
• [6] A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci.Hum Mol Genet. 2013 Oct 1;22(19):4021-9. doi: 10.1093/hmg/ddt248. Epub 2013 Jun 4.
• [7] 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.
• [8] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [9] 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.
• [10] 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.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [13] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [16] 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.
• [17] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [18] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.