Details of Drug Off-Target (DOT)

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

• DOT Name: Proto-oncogene tyrosine-protein kinase ROS (ROS1)
• Synonyms: EC 2.7.10.1; Proto-oncogene c-Ros; Proto-oncogene c-Ros-1; Receptor tyrosine kinase c-ros oncogene 1; c-Ros receptor tyrosine kinase
• Gene Name: ROS1
• Related Disease:
  Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation
  Breast cancer
• UniProt ID: ROS1_HUMAN
• PDB ID: 3ZBF; 4UXL; 7Z5W; 7Z5X
• EC Number: 2.7.10.1
• Pfam ID: PF00041 ; PF07714
• Sequence:
  MKNIYCLIPKLVNFATLGCLWISVVQCTVLNSCLKSCVTNLGQQLDLGTPHNLSEPCIQG
  CHFWNSVDQKNCALKCRESCEVGCSSAEGAYEEEVLENADLPTAPFASSIGSHNMTLRWK
  SANFSGVKYIIQWKYAQLLGSWTYTKTVSRPSYVVKPLHPFTEYIFRVVWIFTAQLQLYS
  PPSPSYRTHPHGVPETAPLIRNIESSSPDTVEVSWDPPQFPGGPILGYNLRLISKNQKLD
  AGTQRTSFQFYSTLPNTIYRFSIAAVNEVGEGPEAESSITTSSSAVQQEEQWLFLSRKTS
  LRKRSLKHLVDEAHCLRLDAIYHNITGISVDVHQQIVYFSEGTLIWAKKAANMSDVSDLR
  IFYRGSGLISSISIDWLYQRMYFIMDELVCVCDLENCSNIEEITPPSISAPQKIVADSYN
  GYVFYLLRDGIYRADLPVPSGRCAEAVRIVESCTLKDFAIKPQAKRIIYFNDTAQVFMST
  FLDGSASHLILPRIPFADVKSFACENNDFLVTDGKVIFQQDALSFNEFIVGCDLSHIEEF
  GFGNLVIFGSSSQLHPLPGRPQELSVLFGSHQALVQWKPPALAIGANVILISDIIELFEL
  GPSAWQNWTYEVKVSTQDPPEVTHIFLNISGTMLNVPELQSAMKYKVSVRASSPKRPGPW
  SEPSVGTTLVPASEPPFIMAVKEDGLWSKPLNSFGPGEFLSSDIGNVSDMDWYNNSLYYS
  DTKGDVFVWLLNGTDISENYHLPSIAGAGALAFEWLGHFLYWAGKTYVIQRQSVLTGHTD
  IVTHVKLLVNDMVVDSVGGYLYWTTLYSVESTRLNGESSLVLQTQPWFSGKKVIALTLDL
  SDGLLYWLVQDSQCIHLYTAVLRGQSTGDTTITEFAAWSTSEISQNALMYYSGRLFWING
  FRIITTQEIGQKTSVSVLEPARFNQFTIIQTSLKPLPGNFSFTPKVIPDSVQESSFRIEG
  NASSFQILWNGPPAVDWGVVFYSVEFSAHSKFLASEQHSLPVFTVEGLEPYALFNLSVTP
  YTYWGKGPKTSLSLRAPETVPSAPENPRIFILPSGKCCNKNEVVVEFRWNKPKHENGVLT
  KFEIFYNISNQSITNKTCEDWIAVNVTPSVMSFQLEGMSPRCFIAFQVRAFTSKGPGPYA
  DVVKSTTSEINPFPHLITLLGNKIVFLDMDQNQVVWTFSAERVISAVCYTADNEMGYYAE
  GDSLFLLHLHNRSSSELFQDSLVFDITVITIDWISRHLYFALKESQNGMQVFDVDLEHKV
  KYPREVKIHNRNSTIISFSVYPLLSRLYWTEVSNFGYQMFYYSIISHTLHRILQPTATNQ
  QNKRNQCSCNVTEFELSGAMAIDTSNLEKPLIYFAKAQEIWAMDLEGCQCWRVITVPAML
  AGKTLVSLTVDGDLIYWIITAKDSTQIYQAKKGNGAIVSQVKALRSRHILAYSSVMQPFP
  DKAFLSLASDTVEPTILNATNTSLTIRLPLAKTNLTWYGITSPTPTYLVYYAEVNDRKNS
  SDLKYRILEFQDSIALIEDLQPFSTYMIQIAVKNYYSDPLEHLPPGKEIWGKTKNGVPEA
  VQLINTTVRSDTSLIISWRESHKPNGPKESVRYQLAISHLALIPETPLRQSEFPNGRLTL
  LVTRLSGGNIYVLKVLACHSEEMWCTESHPVTVEMFNTPEKPYSLVPENTSLQFNWKAPL
  NVNLIRFWVELQKWKYNEFYHVKTSCSQGPAYVCNITNLQPYTSYNVRVVVVYKTGENST
  SLPESFKTKAGVPNKPGIPKLLEGSKNSIQWEKAEDNGCRITYYILEIRKSTSNNLQNQN
  LRWKMTFNGSCSSVCTWKSKNLKGIFQFRVVAANNLGFGEYSGISENIILVGDDFWIPET
  SFILTIIVGIFLVVTIPLTFVWHRRLKNQKSAKEGVTVLINEDKELAELRGLAAGVGLAN
  ACYAIHTLPTQEEIENLPAFPREKLTLRLLLGSGAFGEVYEGTAVDILGVGSGEIKVAVK
  TLKKGSTDQEKIEFLKEAHLMSKFNHPNILKQLGVCLLNEPQYIILELMEGGDLLTYLRK
  ARMATFYGPLLTLVDLVDLCVDISKGCVYLERMHFIHRDLAARNCLVSVKDYTSPRIVKI
  GDFGLARDIYKNDYYRKRGEGLLPVRWMAPESLMDGIFTTQSDVWSFGILIWEILTLGHQ
  PYPAHSNLDVLNYVQTGGRLEPPRNCPDDLWNLMTQCWAQEPDQRPTFHRIQDQLQLFRN
  FFLNSIYKSRDEANNSGVINESFEGEDGDVICLNSDDIMPVALMETKNREGLNYMVLATE
  CGQGEEKSEGPLGSQESESCGLRKEEKEPHADKDFCQEKQVAYCPSGKPEGLNYACLTHS
  GYGDGSD
• Function: Receptor tyrosine kinase (RTK) that plays a role in epithelial cell differentiation and regionalization of the proximal epididymal epithelium. NELL2 is an endogenous ligand for ROS1. Upon endogenous stimulation by NELL2, ROS1 activates the intracellular signaling pathway and triggers epididymal epithelial differentiation and subsequent sperm maturation. May activate several downstream signaling pathways related to cell differentiation, proliferation, growth and survival including the PI3 kinase-mTOR signaling pathway. Mediates the phosphorylation of PTPN11, an activator of this pathway. May also phosphorylate and activate the transcription factor STAT3 to control anchorage-independent cell growth. Mediates the phosphorylation and the activation of VAV3, a guanine nucleotide exchange factor regulating cell morphology. May activate other downstream signaling proteins including AKT1, MAPK1, MAPK3, IRS1 and PLCG2.
• Tissue Specificity: Expressed in brain. Expression is increased in primary gliomas.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation	DIS56JR8	Moderate	Autosomal recessive	[1]
Breast cancer	DIS7DPX1	Limited	Autosomal dominant	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Proto-oncogene tyrosine-protein kinase ROS (ROS1) affects the response to substance of Arsenic trioxide.	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Proto-oncogene tyrosine-protein kinase ROS (ROS1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Proto-oncogene tyrosine-protein kinase ROS (ROS1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Proto-oncogene tyrosine-protein kinase ROS (ROS1).	[5]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Proto-oncogene tyrosine-protein kinase ROS (ROS1).	[6]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Proto-oncogene tyrosine-protein kinase ROS (ROS1).	[7]
Dactinomycin	DM2YGNW	Approved	Dactinomycin increases the expression of Proto-oncogene tyrosine-protein kinase ROS (ROS1).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Proto-oncogene tyrosine-protein kinase ROS (ROS1).	[10]

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 Proto-oncogene tyrosine-protein kinase ROS (ROS1).	[9]

References

• [1] A genomics approach to male infertility. Genet Med. 2020 Dec;22(12):1967-1975. doi: 10.1038/s41436-020-0916-0. Epub 2020 Jul 28.
• [2] 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.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Epigenetic regulation of c-ROS receptor tyrosine kinase expression in malignant gliomas. Cancer Res. 2009 Mar 15;69(6):2180-4. doi: 10.1158/0008-5472.CAN-08-3351. Epub 2009 Mar 10.
• [7] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [8] Response rate of fibrosarcoma cells to cytotoxic drugs on the expression level correlates to the therapeutic response rate of fibrosarcomas and is mediated by regulation of apoptotic pathways. BMC Cancer. 2005 Jul 7;5:74. doi: 10.1186/1471-2407-5-74.
• [9] 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.
• [10] 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.
• [11] Downregulation of ROS1 enhances the therapeutic efficacy of arsenic trioxide in acute myeloid leukemia cell lines. Oncol Lett. 2018 Jun;15(6):9392-9396. doi: 10.3892/ol.2018.8458. Epub 2018 Apr 10.