Target Information
| Target General Information | Top | |||||
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| Target ID |
T69128
(Former ID: TTDNS00597)
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| Target Name |
Proto-oncogene c-Ros (ROS1)
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| Synonyms |
c-Ros receptor tyrosine kinase; Receptor tyrosine kinase c-ros oncogene 1; ROS; Proto-oncogene tyrosine-protein kinase ROS; Proto-oncogene c-Ros-1; MCF3
Click to Show/Hide
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| Gene Name |
ROS1
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Lung cancer [ICD-11: 2C25] | |||||
| 2 | Non-small-cell lung cancer [ICD-11: 2C25] | |||||
| Function |
Orphan receptor tyrosine kinase (RTK) that plays a role in epithelial cell differentiation and regionalization of the proximal epididymal epithelium. 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.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.10.1
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| 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 Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T40XWM | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 4 Approved Drugs | + | ||||
| 1 | Crizotinib | Drug Info | Approved | Non-small-cell lung cancer | [2], [3] | |
| 2 | Entrectinib | Drug Info | Approved | Non-small-cell lung cancer | [4] | |
| 3 | Lorlatinib | Drug Info | Approved | Non-small-cell lung cancer | [5] | |
| 4 | Repotrectinib | Drug Info | Approved | Non-small-cell lung cancer | [6] | |
| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | AB-106 | Drug Info | Phase 2 | Non-small-cell lung cancer | [7] | |
| 2 | DS-6051 | Drug Info | Phase 1 | Solid tumour/cancer | [8] | |
| Patented Agent(s) | [+] 4 Patented Agents | + | ||||
| 1 | Imidazo[1,2-b]pyridazine derivative 1 | Drug Info | Patented | Solid tumour/cancer | [9] | |
| 2 | Imidazo[1,2-b]pyridazine derivative 2 | Drug Info | Patented | Solid tumour/cancer | [9] | |
| 3 | Imidazo[1,2-b]pyridazine derivative 3 | Drug Info | Patented | Solid tumour/cancer | [9] | |
| 4 | PMID28270010-Compound-Figure21-b | Drug Info | Patented | Brain metastases | [9] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | Crizotinib | Drug Info | [1] | |||
| Inhibitor | [+] 11 Inhibitor drugs | + | ||||
| 1 | Entrectinib | Drug Info | [4] | |||
| 2 | Lorlatinib | Drug Info | [5] | |||
| 3 | Repotrectinib | Drug Info | [6] | |||
| 4 | AB-106 | Drug Info | [10] | |||
| 5 | DS-6051 | Drug Info | [11], [12] | |||
| 6 | Carboxamide derivative 4 | Drug Info | [13] | |||
| 7 | Imidazo[1,2-b]pyridazine derivative 1 | Drug Info | [9] | |||
| 8 | Imidazo[1,2-b]pyridazine derivative 2 | Drug Info | [9] | |||
| 9 | Imidazo[1,2-b]pyridazine derivative 3 | Drug Info | [9] | |||
| 10 | PMID28270010-Compound-Figure21-b | Drug Info | [9] | |||
| 11 | PMID24432909C8e | Drug Info | [14] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Crizotinib | Ligand Info | |||||
| Structure Description | Structure of Human ROS1 Kinase Domain in Complex with Crizotinib | PDB:3ZBF | ||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | No | [15] |
| PDB Sequence |
IENLPAFPRE
1943 KLTLRLLLGS1953 GEVYEGTAVD1966 ILGVGSGEIK1976 VAVKTLKKGS1986 TDQEKIEFLK 1996 EAHLMSKFNH2006 PNILKQLGVC2016 LLNEPQYIIL2026 ELMEGGDLLT2036 YLRKARMATF 2046 YGPLLTLVDL2056 VDLCVDISKG2066 CVYLERMHFI2076 HRDLAARNCL2086 VSVKDYTSPR 2096 IVKIGDFGLA2106 RDIYLPVRWM2128 APESLMDGIF2138 TTQSDVWSFG2148 ILIWEILTLG 2158 HQPYPAHSNL2168 DVLNYVQTGG2178 RLEPPRNCPD2188 DLWNLMTQCW2198 AQEPDQRPTF 2208 HRIQDQLQLF2218 RNFFLNSIYK2228 SR
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LEU1951
3.726
VAL1959
4.122
ALA1978
3.488
LYS1980
4.015
LEU2010
3.353
LEU2026
3.870
GLU2027
3.156
LEU2028
3.807
MET2029
3.038
GLU2030
4.932
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| Ligand Name: PF-06463922 | Ligand Info | |||||
| Structure Description | Structure of Human ROS1 Kinase Domain in Complex with PF-06463922 | PDB:4UXL | ||||
| Method | X-ray diffraction | Resolution | 2.40 Å | Mutation | No | [16] |
| PDB Sequence |
IENLPAFPRE
1943 KLTLRLLLGS1953 GAFGEVYEGT1963 AVDILGVGSG1973 EIKVAVKTLK1983 KGSTDQEKIE 1993 FLKEAHLMSK2003 FNHPNILKQL2013 GVCLLNEPQY2023 IILELMEGGD2033 LLTYLRKARM 2043 ATFYGPLLTL2053 VDLVDLCVDI2063 SKGCVYLERM2073 HFIHRDLAAR2083 NCLVSVKDYT 2093 SPRIVKIGDF2103 GLARDIYKEG2121 LLPVRWMAPE2131 SLMDGIFTTQ2141 SDVWSFGILI 2151 WEILTLGHQP2161 YPAHSNLDVL2171 NYVQTGGRLE2181 PPRNCPDDLW2191 NLMTQCWAQE 2201 PDQRPTFHRI2211 QDQLQLFRNF2221 FLNSIYKSR
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LEU1951
3.438
GLY1952
4.188
GLY1954
4.696
VAL1959
3.586
GLU1961
4.322
ALA1978
3.544
LYS1980
4.190
LEU2010
3.837
LEU2026
3.598
GLU2027
2.936
LEU2028
3.523
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Similarity Proteins
Human Tissue Distribution
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Drug Resistance Mutation (DRM) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Spinal Cord Injury | |||||
| References | Top | |||||
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| REF 1 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 2 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4903). | |||||
| REF 3 | 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4. | |||||
| REF 4 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019 | |||||
| REF 5 | 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89. | |||||
| REF 6 | FDA Approved Drug Products from FDA Official Website. 2023. Application Number: 218213 | |||||
| REF 7 | ClinicalTrials.gov (NCT04395677) A Study of AB-106 in Subjects With Advanced NSCLC Harboring ROS1 Fusion Gene. U.S. National Institutes of Health. | |||||
| REF 8 | ClinicalTrials.gov (NCT02279433) A First-in-human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of DS-6051b. U.S. National Institutes of Health. | |||||
| REF 9 | Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part I.Expert Opin Ther Pat. 2017 Jun;27(6):733-751. | |||||
| REF 10 | Clinical pipeline report, company report or official report of AnHeart Therapeutics. | |||||
| REF 11 | National Cancer Institute Drug Dictionary (drug id 766123). | |||||
| REF 12 | ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. Clin Adv Hematol Oncol. 2014 Jul;12(7):429-39. | |||||
| REF 13 | RET kinase inhibitors: a review of recent patents (2012-2015).Expert Opin Ther Pat. 2017 Jan;27(1):91-99. | |||||
| REF 14 | Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib. J Med Chem.> 2014 Feb 27;57(4):1170-87. | |||||
| REF 15 | Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med. 2013 Jun 20;368(25):2395-401. | |||||
| REF 16 | PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations. Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3493-8. | |||||
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