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c-ros oncogene 1, receptor tyrosine kinase

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Target not currently curated in GtoImmuPdb

Target id: 1840

Nomenclature: c-ros oncogene 1, receptor tyrosine kinase

Abbreviated Name: ROS

Family: Type XVII RTKs: ROS receptors

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 2347 6q22.1 ROS1 ROS proto-oncogene 1, receptor tyrosine kinase
Mouse 1 2340 10 26.18 cM Ros1 Ros1 proto-oncogene
Rat 1 2338 20q11 Ros1 ROS proto-oncogene 1 , receptor tyrosine kinase
Previous and Unofficial Names Click here for help
c-ros-1 | heart - derived c - ros - 1 proto - oncogene | MCF3 | ROS1C | ROS proto-oncogene 1 | ROS proto-oncogene 1 , receptor tyrosine kinase
Database Links Click here for help
Alphafold P08922 (Hs), Q78DX7 (Mm), Q63132 (Rn)
BRENDA 2.7.10.1
CATH/Gene3D 2.130.10.10, 2.60.40.10, 2.120.10.30
ChEMBL Target CHEMBL5568 (Hs), CHEMBL2034802 (Mm)
Ensembl Gene ENSG00000047936 (Hs), ENSMUSG00000019893 (Mm), ENSRNOG00000000406 (Rn)
Entrez Gene 6098 (Hs), 19886 (Mm), 25346 (Rn)
Human Protein Atlas ENSG00000047936 (Hs)
KEGG Enzyme 2.7.10.1
KEGG Gene hsa:6098 (Hs), mmu:19886 (Mm), rno:25346 (Rn)
OMIM 165020 (Hs)
Pharos P08922 (Hs)
RefSeq Nucleotide NM_002944 (Hs), NM_011282 (Mm), NM_012874 (Rn)
RefSeq Protein NP_002935 (Hs), NP_035412 (Mm), NP_037006 (Rn)
UniProtKB P08922 (Hs), Q78DX7 (Mm), Q63132 (Rn)
Wikipedia ROS1 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Structure of Human ROS1 Kinase Domain in Complex with PF-06463922
PDB Id:  4UXL
Ligand:  lorlatinib
Resolution:  2.4Å
Species:  Human
References:  12
Enzyme Reaction Click here for help
EC Number: 2.7.10.1

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
lorlatinib Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 11.3 pKi 6
⤷ pKi 11.3 (Ki 5x10-12 M) [6]
compound 8e [PMID: 24432909] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 10.7 pKi 8
⤷ pKi 10.7 (Ki 2x10-11 M) [8]
Description: Value calculated from tight-binding (Morrison) equation for competitive inhibitors tested in a Pfizer mobility shift assay.
zidesamtinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition >7.3 pKi 7
⤷ pKi >7.3 (Ki <5x10-8 M) [7]
Description: Inhibition of ROS1G2032R
repotrectinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 10.1 pIC50 4
⤷ pIC50 10.1 (IC50 7x10-11 M) IC50 for ROS1G2032R is 0.5 nM, and for ROS1D2033N is 0.2 nM [4]
taletrectinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.7 pIC50 9
⤷ pIC50 9.7 (IC50 2x10-10 M) [9]
zidesamtinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.1 pIC50 3
⤷ pIC50 9.1 (IC50 7x10-10 M) [3]
Description: Inhibition of wild-type ROS1 in an enzyme activity assay
gilteritinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition ~8.8 pIC50 10
⤷ pIC50 ~8.8 (IC50 ~1.5x10-9 M) [10]
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 2,11
Key to terms and symbols Click column headers to sort
Target used in screen: ROS1
Ligand Sp. Type Action Value Parameter
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 9.3 pKd
crizotinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.4 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.8 pKd
GSK-1838705A Small molecule or natural product Hs Inhibitor Inhibition 7.8 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.6 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.5 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.5 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.4 pKd
fedratinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.2 pKd
tozasertib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.2 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx

Reference: 1,5
Key to terms and symbols Click column headers to sort
Target used in screen: Ros/ROS(ROS1)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 0.9 3.5 1.5
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.2 1.0 3.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 1.6 94.0 81.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 1.6 21.0 3.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.7 70.0 16.0
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.5 63.0 50.0
GSK-3 inhibitor XIII Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 16.7 84.0 40.0
pazopanib Small molecule or natural product Approved drug Hs Inhibitor Inhibition 17.0
aloisine A Small molecule or natural product Hs Inhibitor Inhibition 26.3 93.0 82.0
PDGF RTK inhibitor Small molecule or natural product Hs Inhibitor Inhibition 26.7 79.0 52.0
Displaying the top 10 most potent ligands  View all ligands in screen »

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1039-45. [PMID:22037377]

2. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1046-51. [PMID:22037378]

3. Drilon A, Horan JC, Tangpeerachaikul A, Besse B, Ou SI, Gadgeel SM, Camidge DR, van der Wekken AJ, Nguyen-Phuong L, Acker A et al.. (2023) NVL-520 Is a Selective, TRK-Sparing, and Brain-Penetrant Inhibitor of ROS1 Fusions and Secondary Resistance Mutations. Cancer Discov, 13 (3): 598-615. [PMID:36511802]

4. Drilon A, Ou SI, Cho BC, Kim DW, Lee J, Lin JJ, Zhu VW, Ahn MJ, Camidge DR, Nguyen J et al.. (2018) Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations. Cancer Discov, 8 (10): 1227-1236. [PMID:30093503]

5. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem J, 451 (2): 313-28. [PMID:23398362]

6. Helen Y. Zou HY, Engstrom LR, Li Q, Lu MW, Tang RW, Wang H, Tsaparikos K, Timofeevski S, Lam J, Yamazaki J et al.. (2013) Abstract A277: PF-06463922, a novel ROS1/ALK inhibitor, demonstrates sub-nanomolar potency against oncogenic ROS1 fusions and capable of blocking the resistant ROS1G2032R mutant in preclinical tumor models. Mol Cancer Ther, (12): A277 Meeting abstract.

7. Horan JC, Tang X, Mente SR, Pelish HE, Shair MD, Tangpeerachaikul A. (2023) Heteroaromatic macrocyclic ether chemotherapeutic agents. Patent number: US11542278. Assignee: Nuvalent, Inc.. Priority date: 29/10/2021. Publication date: 03/01/2023.

8. Huang Q, Johnson TW, Bailey S, Brooun A, Bunker KD, Burke BJ, Collins MR, Cook AS, Cui JJ, Dack KN et al.. (2014) Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib. J Med Chem, 57 (4): 1170-87. [PMID:24432909]

9. Katayama R, Gong B, Togashi N, Miyamoto M, Kiga M, Iwasaki S, Kamai Y, Tominaga Y, Takeda Y, Kagoshima Y et al.. (2019) The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1-G2032R mutation in preclinical models. Nat Commun, 10 (1): 3604. [PMID:31399568]

10. Lee LY, Hernandez D, Rajkhowa T, Smith SC, Raman JR, Nguyen B, Small D, Levis M. (2017) Preclinical studies of gilteritinib, a next-generation FLT3 inhibitor. Blood, 129 (2): 257-260. [PMID:27908881]

11. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem Biol, 17 (11): 1241-9. [PMID:21095574]

12. Zou HY, Li Q, Engstrom LD, West M, Appleman V, Wong KA, McTigue M, Deng YL, Liu W, Brooun A et al.. (2015) PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations. Proc Natl Acad Sci USA, 112 (11): 3493-8. [PMID:25733882]

How to cite this page

Type XVII RTKs: ROS receptors: c-ros oncogene 1, receptor tyrosine kinase. Last modified on 19/04/2023. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=1840.