ROS1

Summary

ROS1 (ROS proto-oncogene 1, receptor tyrosine kinase, HGNC:10261) is a protein-coding gene on chromosome 6q22.1, encoding Proto-oncogene tyrosine-protein kinase ROS (P08922). Receptor tyrosine kinase (RTK) that plays a role in epithelial cell differentiation and regionalization of the proximal epididymal epithelium. In precision oncology, ROS1 G2032R AND v::ROS1 Fusion confers sensitivity to Repotrectinib in Lung Non-small Cell Carcinoma (CIViC Level B); 18 further curated variant–drug associations are listed below.

This proto-oncogene, highly-expressed in a variety of tumor cell lines, belongs to the sevenless subfamily of tyrosine kinase insulin receptor genes. The protein encoded by this gene is a type I integral membrane protein with tyrosine kinase activity. The protein may function as a growth or differentiation factor receptor.

Source: NCBI Gene 6098 — RefSeq curated summary.

At a glance

• Gene–disease (curated): male infertility with azoospermia or oligozoospermia due to single gene mutation (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 63
• Clinical variants (ClinVar): 359 total — 3 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 8
• Druggable target: yes — 41 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 19 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 5 cancer types
• MANE Select transcript: NM_001378902

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10261
Approved symbol	ROS1
Name	ROS proto-oncogene 1, receptor tyrosine kinase
Location	6q22.1
Locus type	gene with protein product
Status	Approved
Aliases	MCF3, ROS, c-ros-1
Ensembl gene	ENSG00000047936
Ensembl biotype	protein_coding
OMIM	165020
Entrez	6098

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000368507, ENST00000368508, ENST00000403284, ENST00000956999, ENST00000957000

RefSeq mRNA: 3 — MANE Select: NM_001378902 NM_001378891, NM_001378902, NM_002944

CCDS: CCDS5116, CCDS93994

Canonical transcript exons

ENST00000368507 — 44 exons

Exon	Start	End
ENSE00000442427	117418462	117418506
ENSE00000442429	117409582	117409642
ENSE00000442431	117403139	117403277
ENSE00000442435	117394162	117394346
ENSE00000442436	117393224	117393321
ENSE00000442443	117366076	117366290
ENSE00000442444	117365581	117365741
ENSE00000442445	117365060	117365204
ENSE00000442447	117360342	117360405
ENSE00000442449	117357804	117358009
ENSE00000442454	117341400	117341632
ENSE00000442455	117341135	117341311
ENSE00000442460	117321259	117321394
ENSE00000442464	117311020	117311117
ENSE00000442466	117308794	117308928
ENSE00000442467	117300974	117301137
ENSE00000762689	117310081	117310281
ENSE00000762693	117317143	117317272
ENSE00000762695	117318188	117318252
ENSE00000762702	117324332	117324415
ENSE00000762704	117326224	117326414
ENSE00000762706	117329329	117329446
ENSE00000762708	117337172	117337340
ENSE00000762714	117342400	117342544
ENSE00000762716	117344060	117344262
ENSE00000762724	117359809	117360011
ENSE00000762730	117362603	117362865
ENSE00000762757	117379059	117379159
ENSE00000762758	117383317	117383508
ENSE00000762759	117385683	117385861
ENSE00000762760	117386889	117386999
ENSE00000762762	117389350	117389846
ENSE00000762766	117394616	117394738
ENSE00000762767	117396188	117396264
ENSE00000762768	117396915	117397116
ENSE00000762770	117404280	117404428
ENSE00000762772	117416258	117416317
ENSE00001209857	117356629	117356915
ENSE00001447299	117352990	117353166
ENSE00001447300	117387780	117387992
ENSE00001447301	117414519	117414545
ENSE00003478828	117319868	117320030
ENSE00003906517	117425534	117425942
ENSE00003908964	117287353	117288802

Expression profiles

Bgee: expression breadth broad, 79 present calls, max score 80.95.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2588 / max 69.9248, expressed in 55 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
75283	0.0647	23
75284	0.0475	19
75286	0.0363	14
75278	0.0334	10
75279	0.0213	8
75285	0.0181	9
75281	0.0154	4
75280	0.0116	6
75282	0.0105	3

Top tissues by expression

263 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
upper lobe of left lung	UBERON:0008952	80.95	gold quality
upper lobe of lung	UBERON:0008948	80.63	gold quality
corpus epididymis	UBERON:0004359	79.17	gold quality
right lung	UBERON:0002167	76.16	gold quality
lung	UBERON:0002048	75.63	gold quality
lower lobe of lung	UBERON:0008949	73.34	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	71.94	silver quality
sperm	CL:0000019	70.54	gold quality
male germ cell	CL:0000015	68.94	gold quality
diaphragm	UBERON:0001103	65.70	gold quality
tendon of biceps brachii	UBERON:0008188	62.94	gold quality
hindlimb stylopod muscle	UBERON:0004252	61.10	gold quality
visceral pleura	UBERON:0002401	60.96	gold quality
secondary oocyte	CL:0000655	60.38	gold quality
decidua	UBERON:0002450	60.01	silver quality
caput epididymis	UBERON:0004358	59.27	gold quality
epithelium of nasopharynx	UBERON:0001951	58.25	gold quality
Brodmann (1909) area 9	UBERON:0013540	57.75	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	57.70	silver quality
triceps brachii	UBERON:0001509	57.17	gold quality
mucosa of paranasal sinus	UBERON:0005030	56.92	gold quality
cauda epididymis	UBERON:0004360	56.28	silver quality
right frontal lobe	UBERON:0002810	56.18	gold quality
gluteal muscle	UBERON:0002000	56.11	gold quality
prefrontal cortex	UBERON:0000451	55.89	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	54.95	gold quality
vena cava	UBERON:0004087	54.61	gold quality
upper leg skin	UBERON:0004262	54.61	gold quality
frontal cortex	UBERON:0001870	54.52	gold quality
myocardium	UBERON:0002349	54.21	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	22.24
E-GEOD-130148	yes	9.11

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, APEX1, CEBPG, FOXO3, HIF1A, HSF2, KLF9, NFE2L2, RBMX, RORA, SP1, SSRP1

Literature-anchored findings (GeneRIF, showing 40)

• Results show that c-ros expression in the human epididymis differs from that in mice and suggest that the unusual morphology of the human epididymis may reflect species differences in gene expression along the excurrent duct. (PMID:15235104)
• inactivation of Ros by SHP-1-mediated dephosphorylation plays a role in the regulation of complex stability (PMID:15456853)
• bcl2 and ROS1 oncogene expression in meningiomas are not concurrent and neither can be ascribed to any histologic subtype or grade of tumor. (PMID:16761743)
• the G –> A polymorphism of ROS1 genotype was independently associated with in-stent restenosis in a Japanese population (PMID:17275003)
• These results suggest that polymorphisms of ABCA1 and ROS1 are determinants of blood pressure and the development of hypertension in Japanese individuals. (PMID:18097620)
• Data show that genotypes for the G–>A (Asp2213Asn) polymorphism (rs529038) of ROS1 was associated (P<0.05) with the prevalence of atherothrombotic cerebral infarction. (PMID:18506375)
• findings do not support the hypothesis that ROS1 rs529038 polymorphism is an important contributing factor in the etiology of CAD in the Greek population (PMID:19863298)
• identification of ROS tyrosine kinase fusions in cholangiocarcinoma (PMID:21253578)
• ROS1 rearrangement defines a molecular subset of NSCLC with distinct clinical characteristics that are similar to those observed in patients with ALK-rearranged NSCLC. (PMID:22215748)
• we discovered previously unidentified kinase fusions that may be promising for molecular-targeted therapy, kinesin family member 5B (KIF5B)-ret proto-oncogene (RET) and coiled-coil domain containing 6 (CCDC6)-RET, in 14 adenocarcinomas (PMID:22327623)
• This study not only identifies ROS1 gene rearrangement as an additional driver mutation in NSCLC. (PMID:22585869)
• ROS1 translocation is associated with lung cancer. (PMID:22617245)
• Expression of CD74-ROS in noninvasive NSCLC cell lines readily conferred invasive properties that paralleled the acquisition of E-Syt1 phosphorylation. (PMID:22659450)
• NSCLC tumors with ROS1 rearrangements are uncommon in the Chinese population and represent a distinct entity of carcinomas. (PMID:22661537)
• These data further support functional roles of aberrant ROS1 protein in tumor progression of non-small cell lung carcinoma. (PMID:22915320)
• Phosphorylated ROS1 activates MSK1 via Erk1/2 in the MAPK pathway, which then induces modifications to histone residues that regulate gene expression by 14-3-3 protein recruitment, leading to a lack of control of breast cancer cell proliferation. (PMID:23292247)
• SLC34A2-ROS1 rearrangement was identified in GC, and the results provide a rationale for investigating the clinical efficacy of ROS1 inhibitors in this unique molecular subset of GC (PMID:23400546)
• ROS1 gene was first identified as an oncogene in NSCLC through a phosphoproteomic screen, leveraging the fact that oncogenic kinases should be highly phosphorylated proteins. (PMID:23401445)
• Aberrant activation of ROS1 represents a new molecular defect in chronic myelomonocytic leukemia. (PMID:23415111)
• All ROS1 fusion-positive lung tumors lacked alteration of EGFR, KRAS, HER2, ALK, and RET genes. (PMID:23426121)
• ROS1 fusion-negative lung cancer patients may have a better survival than ROS1 fusion-positive patients. (PMID:23514723)
• ROS1 expression is significantly lower in proportion to higher histologic grade, higher mitotic counts, lower estrogen receptor expression, and a higher Ki-67 proliferation index in invasive ductal carcinoma of the breast. (PMID:23549810)
• Targeting ROS1 fusion proteins with the small-molecule inhibitor crizotinib is showing promise as an effective therapy in patients with NSCLC whose tumors are positive for these genetic abnormalities. (PMID:23719267)
• The frequency of ROS1 rearrangements in clinically selected patients is higher than that reported for unselected patients. (PMID:23788756)
• ROS1 gene rearrangements are associated with metastatic non–small-cell lung cancer. (PMID:23810364)
• Immunohistochemical ROS1 protein expression in lung adenocarcinoma is 100% sensitive and 92% specific for ROS1 rearrangements by fluorescence in situ hybridization. (PMID:23887156)
• ROS1 rearrangement is associated with non-small-cell lung cancer. (PMID:24128715)
• significance of ROS1 rearrangements in non-small cell lung cancer (PMID:24345493)
• These results suggest that co-inhibition of ROS1 and EGFR may be an effective strategy to combat resistance to targeted therapy in some ROS1 fusion-positive non-small cell lung cancer patients. (PMID:24349229)
• ROS1 translocations are rare events in resected non-small-cell lung cancers from Caucasian patients (PMID:24456475)
• poorer disease-free survival in fusion-positive lung adenocarcinoma patients after curative surgery (PMID:24462463)
• ALK, ROS1 and RET fusions are associated with pathological features of lung adenocarcinoma and are more prevalent in solid-predominant adenocarcinoma. (PMID:24629636)
• Data show that translocations and amplifications of ROS1 gene occur at a similarly low rate in lung cancer brain metastases as reported for primary tumors (PMID:24760415)
• None of 268 gliomas analysed showed the FIG-ROS1(L) rearrangement (PMID:24999209)
• EZR-ROS1 fusion gene is associated with response to therapy in metastatic mediastinum lymph node from a non-small cell lung cancer. (PMID:25230898)
• Six out of 65 (9%) BTC patients were positive for the FIG-ROS1 fusion, comprising two out of 14 (14%) gallbladder carcinoma (GBC) patients and four out of 25 (16%) extrahepatic cholangiocarcinoma (ECC) patients. (PMID:25231053)
• We developed a comprehensive model of acquired resistance to ROS1 inhibitors in non-small cell lung cancer with ROS1 rearrangement and identified cabozantinib as a therapeutic strategy to overcome the resistance. (PMID:25351743)
• ROS1 gene copy number gain status is more common in male patients and in cases with squamous histology in non small cell lung cancer (PMID:25374304)
• GPX1-dependent alterations in oxido-reductive stress promote ROS1 activation and mediate vascular remodeling. (PMID:25401476)
• findings suggest that immunohistochemistry for ROS1 may be useful to support the diagnosis of a subset of inflammatory myofibroblastic tumors (PMID:25612511)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ros1	ENSDARG00000087197
mus_musculus	Ros1	ENSMUSG00000019893
rattus_norvegicus	Ros1	ENSRNOG00000000406
drosophila_melanogaster	sev	FBGN0003366

Paralogs (53): INSRR (ENSG00000027644), MUSK (ENSG00000030304), FLT4 (ENSG00000037280), EPHA3 (ENSG00000044524), LTK (ENSG00000062524), ERBB3 (ENSG00000065361), TIE1 (ENSG00000066056), FGFR2 (ENSG00000066468), FGFR3 (ENSG00000068078), EPHA8 (ENSG00000070886), FGFR1 (ENSG00000077782), EPHA6 (ENSG00000080224), TYRO3 (ENSG00000092445), FLT1 (ENSG00000102755), MET (ENSG00000105976), EPHB6 (ENSG00000106123), PDGFRB (ENSG00000113721), EPHA4 (ENSG00000116106), TEK (ENSG00000120156), FLT3 (ENSG00000122025), KDR (ENSG00000128052), EPHB2 (ENSG00000133216), PDGFRA (ENSG00000134853), EPHA7 (ENSG00000135333), IGF1R (ENSG00000140443), NTRK3 (ENSG00000140538), ERBB2 (ENSG00000141736), EPHA2 (ENSG00000142627), EPHA5 (ENSG00000145242), EGFR (ENSG00000146648), EPHA1 (ENSG00000146904), NTRK2 (ENSG00000148053), MERTK (ENSG00000153208), EPHB1 (ENSG00000154928), KIT (ENSG00000157404), FGFR4 (ENSG00000160867), DDR2 (ENSG00000162733), RYK (ENSG00000163785), MST1R (ENSG00000164078), LMTK2 (ENSG00000164715)

Protein

Protein identifiers

Proto-oncogene tyrosine-protein kinase ROS — P08922 (reviewed: P08922)

Alternative names: Proto-oncogene c-Ros, Proto-oncogene c-Ros-1, Receptor tyrosine kinase c-ros oncogene 1, c-Ros receptor tyrosine kinase

All UniProt accessions (3): P08922, H0Y3T9, Q5H8Y1

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. Interacts with PTPN6 (via SH2 1 domain); the interaction is direct and promotes ROS1 dephosphorylation. Interacts with PTPN11; may activate the PI3 kinase-mTOR signaling pathway. Interacts with VAV3; constitutive interaction mediating VAV3 phosphorylation.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in brain. Expression is increased in primary gliomas.

Post-translational modifications. Phosphorylated. Probably autophosphorylates. Phosphorylation at Tyr-2274 is required for the interaction with PTPN6 that mediates ROS1 dephosphorylation. Phosphorylation at Tyr-2274 stimulates the kinase activity and the activation of the ERK1 signaling cascade. Phosphorylation at Tyr-2274 and/or Tyr-2334 recruits PTPN11.

Disease relevance. A chromosomal aberration involving ROS1 is found in a glioblastoma multiforme sample. An intra-chromosomal deletion del(6)(q21q21) is responsible for the formation of GOPC-ROS1 chimeric protein which is localized to the Golgi and has a constitutive receptor tyrosine kinase activity. A SLC34A2-ROS1 chimeric protein produced in non-small cell lung cancer cells also retains a constitutive kinase activity. A third type of chimeric protein CD74-ROS1 was also identified in those cells.

Activity regulation. Inhibited by dephosphorylation by PTPN6.

Similarity. Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily.

RefSeq proteins (3): NP_001365820, NP_001365831, NP_002935 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000033	LDLR_classB_rpt	Repeat
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR002011	Tyr_kinase_rcpt_2_CS	Conserved_site
IPR003961	FN3_dom	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR011042	6-blade_b-propeller_TolB-like	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020635	Tyr_kinase_cat_dom	Domain
IPR036116	FN3_sf	Homologous_superfamily
IPR050122	RTK	Family

Pfam: PF00041, PF07714

Enzyme classification (BRENDA):

• EC 2.7.10.1 — receptor protein-tyrosine kinase (BRENDA: 44 organisms, 214 substrates, 574 inhibitors, 11 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0011–0.129	4
AC-DYFE-6-CHLORO-W-NHME	0.0051	1
AC-DYFGW-NHME	0.07	1
YFEW	0.232	1

Catalyzed reactions (Rhea), 1 shown:

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)

UniProt features (113 total): sequence variant 31, glycosylation site 30, helix 12, domain 10, strand 10, mutagenesis site 3, binding site 2, topological domain 2, site 2, modified residue 2, sequence conflict 2, signal peptide 1, chain 1, region of interest 1, compositionally biased region 1, active site 1, transmembrane region 1, turn 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
7Z5X	X-RAY DIFFRACTION	2.04
3ZBF	X-RAY DIFFRACTION	2.2
9QEK	X-RAY DIFFRACTION	2.21
7Z5W	X-RAY DIFFRACTION	2.25
4UXL	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08922-F1	72.86	0.07

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 2079 (proton acceptor); 1852–1853 (breakpoint for translocation to form slc34a2-ros1 and cd74-ros1 fusion proteins); 1880–1881 (breakpoint for translocation to form gopc-ros1 fusion protein)

Ligand- & substrate-binding residues (2): 1951–1959; 1980

Post-translational modifications (2): 2274, 2334

Glycosylation sites (30): 52, 114, 123, 324, 352, 396, 471, 607, 628, 706, 714, 732, 939, 961, 1015, 1087, 1090, 1095, 1211, 1272 …

Mutagenesis-validated functional residues (3):

Position	Phenotype
1980	loss of kinase activity.
2274	loss of phosphorylation at y-2274 and loss of interaction with ptpn11.
2334	loss of phosphorylation at y-2334 and loss of interaction with ptpn11.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 0 (showing top):

GO Biological Process (13): regulation of cell growth (GO:0001558), columnar/cuboidal epithelial cell development (GO:0002066), protein phosphorylation (GO:0006468), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), spermatogenesis (GO:0007283), cell differentiation (GO:0030154), regulation of TOR signaling (GO:0032006), regulation of ERK1 and ERK2 cascade (GO:0070372), signal transduction (GO:0007165), gene expression (GO:0010467), negative regulation of gene expression (GO:0010629), regulation of phosphate transport (GO:0010966), regulation of intracellular signal transduction (GO:1902531)

GO Molecular Function (9): protein tyrosine kinase activity (GO:0004713), transmembrane receptor protein tyrosine kinase activity (GO:0004714), ATP binding (GO:0005524), protein phosphatase binding (GO:0019903), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (5): plasma membrane (GO:0005886), membrane (GO:0016020), signaling receptor complex (GO:0043235), cell surface (GO:0009986), perinuclear region of cytoplasm (GO:0048471)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
epithelial cell development	1
columnar/cuboidal epithelial cell differentiation	1
phosphorylation	1
protein modification process	1
enzyme-linked receptor protein signaling pathway	1
developmental process involved in reproduction	1
male gamete generation	1
cellular developmental process	1
TOR signaling	1
regulation of intracellular signal transduction	1
regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
macromolecule biosynthetic process	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
phosphate ion transport	1
regulation of transport	1
regulation of signal transduction	1
intracellular signal transduction	1
protein kinase activity	1
protein tyrosine kinase activity	1
transmembrane receptor protein kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
phosphatase binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1

Protein interactions and networks

STRING

2070 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ROS1	EML4	Q9HC35	921
ROS1	OR13G1	Q8NGZ3	915
ROS1	TAS2R50	P59544	908
ROS1	GOPC	Q9HD26	902
ROS1	KRAS	P01116	847
ROS1	PALLD	Q8WX93	839
ROS1	SLC34A2	O95436	816
ROS1	RET	P07949	784
ROS1	CD74	P04233	776
ROS1	TPM3	P06753	766
ROS1	CD274	Q9NZQ7	760
ROS1	PIK3CA	P42336	728
ROS1	LRIG3	Q6UXM1	724
ROS1	NRAS	P01111	705
ROS1	SDC4	P31431	695

IntAct

34 interactions, top by confidence:

A	B	Type	Score
PTPN6	ROS1	psi-mi:“MI:0203”(dephosphorylation reaction)	0.640
PTPN6	ROS1	psi-mi:“MI:0914”(association)	0.640
PTPN1	ROS1	psi-mi:“MI:0203”(dephosphorylation reaction)	0.440
PKM	ROS1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
ROS1	LACTB	psi-mi:“MI:0915”(physical association)	0.400
ROS1	Ahnak	psi-mi:“MI:0914”(association)	0.350
ROS1	ODAD3	psi-mi:“MI:0914”(association)	0.350
SHANK3	IGKV3D-15	psi-mi:“MI:0914”(association)	0.350
ROS1	NDUFA4	psi-mi:“MI:2364”(proximity)	0.270
AKT1	ROS1	psi-mi:“MI:2364”(proximity)	0.270
ROS1	BRAF	psi-mi:“MI:2364”(proximity)	0.270
FBXW7	ROS1	psi-mi:“MI:2364”(proximity)	0.270
SMAD4	ROS1	psi-mi:“MI:2364”(proximity)	0.270
ROS1	SMARCA4	psi-mi:“MI:2364”(proximity)	0.270
SMARCA4	ROS1	psi-mi:“MI:2364”(proximity)	0.270
SPOP	ROS1	psi-mi:“MI:2364”(proximity)	0.270
ROS1	SPOP	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (106): GRB2 (Co-fractionation), FGFR4 (FRET), PTPN6 (Two-hybrid), PTPN11 (Two-hybrid), ROS1 (Biochemical Activity), PTPN6 (Affinity Capture-Western), ROS1 (Affinity Capture-Western), LACTB (Proximity Label-MS), VAV3 (Affinity Capture-Western), HSPA1B (Proximity Label-MS), PRKDC (Proximity Label-MS), HYOU1 (Proximity Label-MS), SMC3 (Proximity Label-MS), DNAJB11 (Proximity Label-MS), NSUN2 (Proximity Label-MS)

ESM2 similar proteins: A2AED3, B0CLX4, B2RU80, B3DK56, B3EX02, E2RK30, F1NWE3, O14522, O70458, O70535, O88488, P08922, P08941, P08F94, P0C5E4, P17948, P20352, P23467, P28827, P28828, P35822, P35969, P35992, P42702, P42703, P53767, P97378, Q15262, Q2EY13, Q2EY15, Q2VWP7, Q2VWP9, Q589G5, Q5RFR6, Q5VJ70, Q5VTL7, Q5XNR9, Q62959, Q63132, Q65Z14

Diamond homologs: A0A0K3AV08, A7J1T0, A7J1T2, A7MBB4, A8X775, D3ZG83, G5EE56, H2KZW3, O01700, O19064, O22558, O43283, O54967, O60674, P00529, P00533, P00534, P00535, P03949, P04412, P06239, P06240, P08069, P08922, P08941, P09760, P09769, P11273, P11362, P13388, P14234, P14616, P14617, P16092, P16591, P18461, P21802, P21803, P21804, P22607

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
PTPN6	down-regulates	ROS1	dephosphorylation
PTPN1	down-regulates	ROS1	dephosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 17 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of gene expression	5	13.8×	2e-03

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

ROS1 is a receptor tyrosine kinase that is frequently involved in genetic rearrangement in a variety of human cancers (e.g. NSCLC, gastric cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, angiosarcoma…). The resulting fusion protein harbors the constitutively active ROS1 kinase domain and drives cellular proliferation (Davies et. al.). In NSCLC about 1% harbor a ROS1 rearrangement. These patients are predominantely female and have a lower T-stage (Warth et. al.). Treatment with crizotinib leads to a reported objective response rate of appr. 70% and a median duration of response of 18 months (Shaw et. al.). Resistance mechanisms to crizotinib have been described and involve mutations in the kinase domain. More selective inhibitors of ROS1 might overcome this resistance (Davare et. al.).

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 5 cancer types — HCC, HNSC, OVT, PRAD, STAD.

Clinical variants and AI predictions

ClinVar

359 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	253
Likely benign	33
Benign	41

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
2431087	NM_001378902.1(ROS1):c.3388G>A (p.Gly1130Arg)	Pathogenic
376139	NM_001378902.1(ROS1):c.6076G>A (p.Gly2026Arg)	Pathogenic
599588	NM_001378902.1(ROS1):c.4583del (p.Asn1528fs)	Pathogenic
2690965	NM_001378902.1(ROS1):c.5588dup (p.Ile1864fs)	Likely pathogenic
2690966	NM_001378902.1(ROS1):c.3611T>A (p.Leu1204Ter)	Likely pathogenic

SpliceAI

7976 predictions. Top by Δscore:

Variant	Effect	Δscore
6:117288800:CAC:C	acceptor_gain	1.0000
6:117288803:C:CC	acceptor_gain	1.0000
6:117288803:C:CG	acceptor_loss	1.0000
6:117311113:TAAAA:T	acceptor_gain	1.0000
6:117311118:C:CC	acceptor_gain	1.0000
6:117318253:C:CC	acceptor_gain	1.0000
6:117320031:C:CC	acceptor_gain	1.0000
6:117321257:A:AC	donor_gain	1.0000
6:117321258:C:CC	donor_gain	1.0000
6:117321395:C:CC	acceptor_gain	1.0000
6:117353033:ACT:A	donor_gain	1.0000
6:117353034:CTC:C	donor_gain	1.0000
6:117383363:T:A	donor_gain	1.0000
6:117383384:T:A	donor_gain	1.0000
6:117386027:CTTA:C	donor_gain	1.0000
6:117386029:TA:T	donor_gain	1.0000
6:117386030:AA:A	donor_gain	1.0000
6:117386030:AAC:A	donor_gain	1.0000
6:117386030:AACC:A	donor_gain	1.0000
6:117288801:AC:A	acceptor_gain	0.9900
6:117288802:CC:C	acceptor_gain	0.9900
6:117288805:G:C	acceptor_gain	0.9900
6:117288805:G:GC	acceptor_gain	0.9900
6:117301478:C:CT	donor_gain	0.9900
6:117308793:CAGAT:C	donor_gain	0.9900
6:117310080:CCATA:C	donor_gain	0.9900
6:117310279:TCC:T	acceptor_gain	0.9900
6:117310280:CC:C	acceptor_gain	0.9900
6:117310280:CCC:C	acceptor_gain	0.9900
6:117310280:CCCTG:C	acceptor_loss	0.9900

AlphaMissense

15390 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:117310136:A:G	W2127R	1.000
6:117310136:A:T	W2127R	1.000
6:117310279:T:G	D2079A	1.000
6:117310082:A:G	W2145R	0.999
6:117310082:A:T	W2145R	0.999
6:117310134:C:A	W2127C	0.999
6:117310134:C:G	W2127C	0.999
6:117310209:G:C	D2102E	0.999
6:117310209:G:T	D2102E	0.999
6:117310210:T:A	D2102V	0.999
6:117310210:T:C	D2102G	0.999
6:117310210:T:G	D2102A	0.999
6:117310211:C:G	D2102H	0.999
6:117310213:C:T	G2101E	0.999
6:117310263:A:C	N2084K	0.999
6:117310263:A:T	N2084K	0.999
6:117310265:T:C	N2084D	0.999
6:117310267:C:A	R2083I	0.999
6:117310267:C:G	R2083T	0.999
6:117310279:T:A	D2079V	0.999
6:117310279:T:C	D2079G	0.999
6:117319868:C:A	K1980N	0.999
6:117319868:C:G	K1980N	0.999
6:117319940:A:C	F1956L	0.999
6:117319940:A:T	F1956L	0.999
6:117319942:A:G	F1956L	0.999
6:117308905:T:A	E2153V	0.998
6:117310101:G:C	F2138L	0.998
6:117310101:G:T	F2138L	0.998
6:117310103:A:G	F2138L	0.998

dbSNP variants (sampled 300 via entrez): RS1000059640 (6:117398896 C>A,T), RS1000064711 (6:117312253 T>A,C,G), RS1000070138 (6:117313474 G>A), RS1000083246 (6:117388946 C>T), RS1000091670 (6:117371994 C>T), RS1000116917 (6:117354934 A>G), RS1000153 (6:117337842 C>T), RS1000154 (6:117337863 A>G), RS1000163110 (6:117305339 G>T), RS1000174699 (6:117426449 T>G), RS1000220557 (6:117337721 T>C), RS1000244856 (6:117392571 T>C), RS1000288332 (6:117416913 C>A), RS1000305085 (6:117366057 C>A,T), RS1000309082 (6:117317730 T>C)

Disease associations

OMIM: gene MIM:165020 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
male infertility with azoospermia or oligozoospermia due to single gene mutation	Moderate	Autosomal recessive
breast cancer	Limited	Autosomal dominant

Mondo (5): lung adenocarcinoma (MONDO:0005061), squamous cell carcinoma (MONDO:0005096), lung sarcomatoid carcinoma (MONDO:0006279), breast cancer (MONDO:0007254), (MONDO:0018393)

Orphanet (2): Male infertility with azoospermia or oligozoospermia due to single gene mutation (Orphanet:399805), NON RARE IN EUROPE: Adenocarcinoma of the lung (Orphanet:415268)

HPO phenotypes

8 total (8 of 8 shown, HPO-id order):

HPO	Term
HP:0000952	Jaundice
HP:0000989	Pruritus
HP:0001945	Fever
HP:0002027	Abdominal pain
HP:0002039	Anorexia
HP:0011985	Acholic stools
HP:0012378	Fatigue
HP:0100574	Biliary tract neoplasm

GWAS associations

63 associations (top):

Study	Trait	p-value
GCST001740_6	Lung cancer	4.000000e-10
GCST001890_7	QT interval (drug interaction)	8.000000e-06
GCST003542_92	Night sleep phenotypes	2.000000e-06
GCST004731_1	Facial emotion recognition (fearful faces)	1.000000e-06
GCST004744_9	Lung adenocarcinoma	7.000000e-08
GCST008103_77	Bipolar disorder	9.000000e-07
GCST009086_2	Pneumococcal meningitis	9.000000e-07
GCST010796_1702	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-19
GCST010796_1703	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-19
GCST010796_1704	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-19
GCST010796_1705	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-19
GCST010796_1706	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-20
GCST010796_1707	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-21
GCST010796_1708	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-22
GCST010796_1709	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-27
GCST010796_1710	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-29
GCST010796_1711	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-25
GCST010796_1712	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-28
GCST010796_1713	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-30
GCST010796_1714	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-34
GCST010796_1715	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-33
GCST010796_1716	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-32
GCST010796_1717	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-28
GCST010796_1718	Electrocardiogram morphology (amplitude at temporal datapoints)	6.000000e-28
GCST010796_1719	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-26
GCST010796_1720	Electrocardiogram morphology (amplitude at temporal datapoints)	8.000000e-24
GCST010796_1721	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-24
GCST010796_1722	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-26
GCST010796_1723	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-26
GCST010796_1724	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-22

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004682	QT interval
EFO:0008329	facial emotion recognition measurement
EFO:0004327	electrocardiography

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D002294	Carcinoma, Squamous Cell	C04.557.470.200.400; C04.557.470.700.400

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (6): CHEMBL4680045 (CHIMERIC PROTEIN), CHEMBL4680046 (CHIMERIC PROTEIN), CHEMBL4748222 (PROTEIN-PROTEIN INTERACTION), CHEMBL5303568 (CHIMERIC PROTEIN), CHEMBL5483088 (CHIMERIC PROTEIN), CHEMBL5568 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

41 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 271,645 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL3286830	LORLATINIB	4	3,598
CHEMBL3545311	BRIGATINIB	4	5,634
CHEMBL4298138	REPOTRECTINIB	4	1,038
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1738797	ALECTINIB	4	6,731
CHEMBL1834657	INFIGRATINIB PHOSPHATE	4	285
CHEMBL1852688	INFIGRATINIB	4	2,209
CHEMBL1983268	ENTRECTINIB	4	3,510
CHEMBL2403108	CERITINIB	4	8,551
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL3889654	LAROTRECTINIB	4	1,850
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL58	MITOXANTRONE	4	166,878
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL3265032	ENTOSPLETINIB	3	1,628
CHEMBL483158	ALISERTIB	3	2,305
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3
CHEMBL1230609	FORETINIB	2
CHEMBL119385	NEFLAMAPIMOD	2
CHEMBL1738757	REBASTINIB	2
CHEMBL1967878	CENISERTIB	2
CHEMBL1980297	ILORASERTIB	2
CHEMBL253969	OSI-632	2
CHEMBL3818247	DALMELITINIB	2
CHEMBL4297627	SELITRECTINIB	2
CHEMBL475251	R-406	2

Clinical evidence (CIViC)

Drug × variant × indication: 19 predictive associations from 23 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
ROS1 G2032R AND v::ROS1 Fusion	Repotrectinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID12022
ROS1 G2032R AND v::ROS1 Fusion	Taletrectinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID12236
ROS1 G2032R	Crizotinib	Lung Non-small Cell Carcinoma	Resistance	CIViC B	EID7684 +3
ROS1 G2032R	Repotrectinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC C	EID7687
ROS1 G2032R	Crizotinib	Lung Adenocarcinoma	Resistance	CIViC C	EID2934
ROS1 G2032R AND CD74::ROS1 Fusion	Crizotinib	Lung Adenocarcinoma	Resistance	CIViC C	EID1100
ROS1 G2032R AND CD74::ROS1 Fusion	Crizotinib	Lung Non-small Cell Carcinoma	Resistance	CIViC C	EID1254
ROS1 G2032R AND CD74::ROS1 Fusion	Cabozantinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC D	EID1101
ROS1 G2032R AND CD74::ROS1 Fusion	Foretinib + Cabozantinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC D	EID1249
ROS1 G2032R AND CD74::ROS1 Fusion	Foretinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC D	EID1255
ROS1 G2032R AND SLC4A4::ROS1 Fusion	DS-6501b	Lung Adenocarcinoma	Sensitivity/Response	CIViC D	EID7538
ROS1 G2032R AND v::ROS1 Fusion	Lorlatinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC D	EID1251
ROS1 G2101A AND CD74::ROS1 Fusion	Foretinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC D	EID1260
ROS1 L2026M AND CD74::ROS1 Fusion	Lorlatinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC D	EID1253
ROS1 L2026M AND CD74::ROS1 Fusion	Foretinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC D	EID1258
ROS1 L2026M AND CD74::ROS1 Fusion	Crizotinib	Lung Non-small Cell Carcinoma	Resistance	CIViC D	EID1252 +1
ROS1 G2032R AND CD74::ROS1 Fusion	Crizotinib + AZD3463 + Ceritinib + Brigatinib	Lung Non-small Cell Carcinoma	Resistance	CIViC D	EID1250
ROS1 G2101A AND CD74::ROS1 Fusion	Crizotinib	Lung Non-small Cell Carcinoma	Resistance	CIViC D	EID1259
ROS1 L2155S AND CD74::ROS1 Fusion	ALK Inhibitor TAE684 + Crizotinib + Foretinib	Lung Non-small Cell Carcinoma	Resistance	CIViC D	EID1256

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Type XVII RTKs: ROS receptors

Most potent curated ligand interactions (6 total), top 6:

Ligand	Action	Affinity	Parameter
lorlatinib	Inhibition	11.3	pKi
compound 8e [PMID: 24432909]	Inhibition	10.7	pKi
repotrectinib	Inhibition	10.15	pIC50
taletrectinib	Inhibition	9.7	pIC50
gilteritinib	Inhibition	8.82	pIC50
zidesamtinib	Inhibition	7.3	pKi

Binding affinities (BindingDB)

42 measured of 66 human assays (66 total across all organisms); most potent 42 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
5-[(4-hydroxycyclohexyl)amino]-3-[4-(4-methylpiperazin-1-yl)anilino]-6-propan-2-ylpyrazine-2-carboxamide	IC50	0.23 nM	US-8969336: Diamino heterocyclic carboxamide compound
3-[3-methoxy-4-(4-methylpiperazin-1-yl)anilino]-5-(oxan-4-ylamino)-6-propan-2-ylpyrazine-2-carboxamide	IC50	0.29 nM	US-8969336: Diamino heterocyclic carboxamide compound
6-ethyl-5-[(4-hydroxycyclohexyl)amino]-3-[3-methyl-4-(4-propan-2-ylpiperazin-1-yl)anilino]pyrazine-2-carboxamide	IC50	0.37 nM	US-8969336: Diamino heterocyclic carboxamide compound
6-ethyl-5-[(4-hydroxycyclohexyl)amino]-3-[4-(4-methylpiperazin-1-yl)anilino]pyrazine-2-carboxamide	IC50	0.4 nM	US-8969336: Diamino heterocyclic carboxamide compound
3-[4-(4-methylpiperazin-1-yl)anilino]-5-(oxan-4-ylamino)-6-propan-2-ylpyrazine-2-carboxamide	IC50	0.41 nM	US-8969336: Diamino heterocyclic carboxamide compound
3-[4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]-5-(oxan-4-ylamino)-6-propan-2-ylpyrazine-2-carboxamide	IC50	0.51 nM	US-8969336: Diamino heterocyclic carboxamide compound
5-[(4-hydroxycyclohexyl)amino]-3-[4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)anilino]-6-propan-2-ylpyrazine-2-carboxamide	IC50	0.51 nM	US-8969336: Diamino heterocyclic carboxamide compound
6-ethyl-3-[3-fluoro-4-(4-methylpiperazin-1-yl)anilino]-5-(oxan-4-ylamino)pyrazine-2-carboxamide	IC50	0.58 nM	US-8969336: Diamino heterocyclic carboxamide compound
6-ethyl-5-[(4-hydroxycyclohexyl)amino]-3-[3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]pyrazine-2-carboxamide	IC50	0.65 nM	US-8969336: Diamino heterocyclic carboxamide compound
6-ethyl-5-[(4-hydroxy-4-methylcyclohexyl)amino]-3-[3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]pyrazine-2-carboxamide	IC50	0.78 nM	US-8969336: Diamino heterocyclic carboxamide compound
6-ethyl-5-[(4-hydroxycyclohexyl)amino]-3-[4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]pyrazine-2-carboxamide	IC50	0.86 nM	US-8969336: Diamino heterocyclic carboxamide compound
6-ethyl-5-[(4-hydroxy-4-methylcyclohexyl)amino]-3-[3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]pyrazine-2-carboxamide	IC50	0.86 nM	US-8969336: Diamino heterocyclic carboxamide compound
6-ethyl-5-[(4-hydroxycyclohexyl)amino]-3-[4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)anilino]pyrazine-2-carboxamide	IC50	1 nM	US-8969336: Diamino heterocyclic carboxamide compound
3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	IC50	1.18 nM	US-8822500: Tyrosine kinase inhibitors
6-ethyl-3-[3-methyl-4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]anilino]-5-(oxan-4-ylamino)pyrazine-2-carboxamide	IC50	1.2 nM	US-8969336: Diamino heterocyclic carboxamide compound
6-ethyl-3-[3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]-5-(oxan-4-ylamino)pyrazine-2-carboxamide	IC50	1.3 nM	US-8969336: Diamino heterocyclic carboxamide compound
6-chloro-5-[(4-hydroxycyclohexyl)amino]-3-[3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]pyrazine-2-carboxamide	IC50	1.6 nM	US-8969336: Diamino heterocyclic carboxamide compound
Staurosporine	KD	1.7 nM
6-ethyl-3-[4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]-5-(oxan-4-ylamino)pyrazine-2-carboxamide	IC50	1.9 nM	US-8969336: Diamino heterocyclic carboxamide compound
Gilteritinib	IC50	1.9 nM	US-8969336: Diamino heterocyclic carboxamide compound
6-[2-(dimethylamino)ethyl]-2-[2-oxo-4-[[(2S)-1-(2,3,5,6-tetrafluorophenyl)propan-2-yl]amino]piperidin-3-yl]-3,5-dihydropyrrolo[3,4-f]benzimidazol-7-one	IC50	2.06 nM	US-8822500: Tyrosine kinase inhibitors
N-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethyl]-3-(5,5-dimethyl-2H-1,2,4-oxadiazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine	IC50	2.75 nM	US-12435089: 3-oxadiazolyl substituted pyrazolo[1,5,a]pyrimidines for ROS1, NTRK, and ALK mediated diseases
N-[(1R)-1-(2-bromo-5-fluorophenyl)ethyl]-3-(5,5-dimethyl-2H-1,2,4-oxadiazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine	IC50	2.75 nM	US-12435089: 3-oxadiazolyl substituted pyrazolo[1,5,a]pyrimidines for ROS1, NTRK, and ALK mediated diseases
N-[(1R)-1-(2-chlorophenyl)ethyl]-3-(5,5-dimethyl-2H-1,2,4-oxadiazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine	IC50	2.75 nM	US-12435089: 3-oxadiazolyl substituted pyrazolo[1,5,a]pyrimidines for ROS1, NTRK, and ALK mediated diseases
N-[(1R)-1-(3,5-difluorophenyl)ethyl]-3-(5,5-dimethyl-2H-1,2,4-oxadiazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine	IC50	2.75 nM	US-12435089: 3-oxadiazolyl substituted pyrazolo[1,5,a]pyrimidines for ROS1, NTRK, and ALK mediated diseases
3-(5,5-dimethyl-2H-1,2,4-oxadiazol-3-yl)-N-[(1R)-1-(5-fluoro-2-methylphenyl)ethyl]pyrazolo[1,5-a]pyrimidin-5-amine	IC50	2.75 nM	US-12435089: 3-oxadiazolyl substituted pyrazolo[1,5,a]pyrimidines for ROS1, NTRK, and ALK mediated diseases
4-fluoro-2-[(1R)-1-[[3-(5-methyl-1,2,4-oxadiazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]ethyl]phenol	IC50	2.75 nM	US-12435089: 3-oxadiazolyl substituted pyrazolo[1,5,a]pyrimidines for ROS1, NTRK, and ALK mediated diseases
3-[5-[(1R)-1-(5-fluoro-2-methoxyphenyl)ethoxy]pyrazolo[1,5-a]pyrimidin-3-yl]-5,5-dimethyl-2H-1,2,4-oxadiazole	IC50	2.75 nM	US-12435089: 3-oxadiazolyl substituted pyrazolo[1,5,a]pyrimidines for ROS1, NTRK, and ALK mediated diseases
6-(1-methylpiperidin-4-yl)-2-[2-oxo-4-[[(2S)-1-(2,3,5,6-tetrafluorophenyl)propan-2-yl]amino]piperidin-3-yl]-3,5-dihydropyrrolo[3,4-f]benzimidazol-7-one	IC50	3.48 nM	US-8822500: Tyrosine kinase inhibitors
US8822500, [24A]	IC50	5.99 nM	US-8822500: Tyrosine kinase inhibitors
(3R)-6-fluoro-3-methyl-10-oxa-2,13,17,18,21-pentazatetracyclo[13.5.2.04,9.018,22]docosa-1(21),4(9),5,7,15(22),16,19-heptaen-14-one	KD	6.8 nM	US-10246466: Diaryl macrocycles as modulators of protein kinases
6-[2-(dimethylamino)ethyl]-2-[2-oxo-4-[[(2S)-1-(2,3,5,6-tetrafluorophenyl)propan-2-yl]amino]piperidin-3-yl]-3H-pyrrolo[3,4-f]benzimidazole-5,7-dione	IC50	14 nM	US-8822500: Tyrosine kinase inhibitors
6-fluoro-2-methyl-10-oxa-2,13,17,18,21-pentazatetracyclo[13.5.2.04,9.018,22]docosa-1(21),4(9),5,7,15(22),16,19-heptaen-14-one	KD	80 nM	US-10246466: Diaryl macrocycles as modulators of protein kinases
5-chloro-6-fluoro-2-methyl-10-oxa-2,13,17,18,21-pentazatetracyclo[13.5.2.04,9.018,22]docosa-1(21),4(9),5,7,15(22),16,19-heptaen-14-one	KD	180 nM	US-10246466: Diaryl macrocycles as modulators of protein kinases
PKC-412	KD	190 nM
5-chloro-6-fluoro-3-methyl-10-oxa-2,13,17,18,21-pentazatetracyclo[13.5.2.04,9.018,22]docosa-1(21),4(9),5,7,15(22),16,19-heptaen-14-one	KD	270 nM	US-10246466: Diaryl macrocycles as modulators of protein kinases
4-[[7-[2,6-bis(fluoranyl)phenyl]-9-chloranyl-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid	KD	300 nM
6-fluoro-2,16-dimethyl-10-oxa-2,13,17,18,21-pentazatetracyclo[13.5.2.04,9.018,22]docosa-1(21),4(9),5,7,15(22),16,19-heptaen-14-one	KD	600 nM	US-10246466: Diaryl macrocycles as modulators of protein kinases
N-[4-({4-[(3-methyl-1H-pyrazol-5-yl)amino]-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide	KD	1100 nM
1-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea	KD	1400 nM
US8822500, [18]	IC50	2000 nM	US-8822500: Tyrosine kinase inhibitors
5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2-methylbenzene-1-sulfonamide	KD	2900 nM

ChEMBL bioactivities

590 potent at pChembl≥5 of 600 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.70	Ki	0.02	nM	CHEMBL3128069
10.15	IC50	0.07	nM	REPOTRECTINIB
10.15	IC50	0.07	nM	STAUROSPORINE
10.00	Ki	0.1	nM	LORLATINIB
10.00	Ki	0.1	nM	CHEMBL5712062
9.85	IC50	0.141	nM	STAUROSPORINE
9.84	IC50	0.145	nM	STAUROSPORINE
9.83	IC50	0.149	nM	STAUROSPORINE
9.77	IC50	0.17	nM	REPOTRECTINIB
9.72	IC50	0.19	nM	LORLATINIB
9.72	IC50	0.19	nM	CHEMBL5712062
9.70	IC50	0.2	nM	STAUROSPORINE
9.70	IC50	0.2	nM	CHEMBL5093999
9.70	IC50	0.2	nM	ENTRECTINIB
9.70	IC50	0.2	nM	CHEMBL5884156
9.69	IC50	0.205	nM	CHEMBL3671311
9.64	IC50	0.23	nM	CHEMBL3687195
9.64	IC50	0.23	nM	CHEMBL4454732
9.64	IC50	0.23	nM	LORLATINIB
9.61	IC50	0.248	nM	CHEMBL1980995
9.54	IC50	0.29	nM	CHEMBL3687223
9.54	IC50	0.29	nM	CHEMBL4438727
9.52	IC50	0.3	nM	CHEMBL3671309
9.52	IC50	0.3	nM	CHEMBL5997227
9.52	IC50	0.3	nM	CHEMBL5945078
9.52	IC50	0.3	nM	LORLATINIB
9.47	IC50	0.34	nM	CHEMBL5630153
9.43	IC50	0.37	nM	CHEMBL3687210
9.43	IC50	0.37	nM	CHEMBL4528166
9.40	IC50	0.4	nM	CHEMBL3687191
9.40	Ki	0.4	nM	CERITINIB
9.40	IC50	0.4	nM	CHEMBL4441604
9.40	IC50	0.4	nM	LORLATINIB
9.40	Ki	0.3981	nM	CHEMBL1993661
9.39	IC50	0.41	nM	CHEMBL3687224
9.39	IC50	0.41	nM	CHEMBL4591953
9.37	IC50	0.43	nM	CHEMBL4470529
9.36	IC50	0.436	nM	CHEMBL3671310
9.31	Kd	0.49	nM	TAE-684
9.30	IC50	0.5	nM	SELITRECTINIB
9.30	IC50	0.5	nM	CHEMBL5884156
9.30	Ki	0.5012	nM	CHEMBL1980995
9.29	IC50	0.51	nM	CHEMBL3687205
9.29	IC50	0.51	nM	CHEMBL3687221
9.29	IC50	0.51	nM	CHEMBL4465573
9.29	IC50	0.51	nM	CHEMBL4483656
9.24	IC50	0.58	nM	CHEMBL3687222
9.24	IC50	0.58	nM	CHEMBL4461418
9.22	Ki	0.6	nM	CRIZOTINIB
9.22	IC50	0.6	nM	CHEMBL5750604

PubChem BioAssay actives

281 with measured affinity, of 1677 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(16R)-19-amino-13-fluoro-4,8,16-trimethyl-9-oxo-17-oxa-4,5,8,20-tetrazatetracyclo[16.3.1.02,6.010,15]docosa-1(22),2,5,11,13,18,20-heptaene-3-carbonitrile	2187694: Binding affinity to recombinant human ROS1 assessed as inhibition constant in presence of ATP by microfluidic mobility shift assay	ki	<0.0001	uM
Lorlatinib	1153110: Inhibition of ROS1 (unknown origin) by off-chip mobility shift assay	ki	<0.0001	uM
(2R)-2-[5-[6-amino-5-[(1R)-1-[5-fluoro-2-(triazol-2-yl)phenyl]ethoxy]-3-pyridinyl]-4-methyl-1,3-thiazol-2-yl]propane-1,2-diol	1074707: Inhibition of ROS1 (unknown origin) by Pfizer mobility shift assay	ki	<0.0001	uM
Repotrectinib	1812888: Inhibition of human ROS1 using KKKSPGEYVNIEFG as substrate in presence of ATP by radiometric HotSpot kinase assay	ic50	0.0001	uM
(17R)-20-amino-14-fluoro-5,9,17-trimethyl-10-oxo-18-oxa-5,6,9,21-tetrazatetracyclo[17.3.1.03,7.011,16]tricosa-1(23),3,6,11(16),12,14,19,21-octaene-4-carbonitrile	1579888: Inhibition of ROS1 (unknown origin)	ki	0.0001	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1531869: Inhibition of human ROS using KKKSPGEYVNIEFG as substrate by [gamma-33P]-ATP assay	ic50	0.0001	uM
(7R)-10-fluorospiro[14-oxa-2,12,17,21,22,25-hexazapentacyclo[17.5.2.02,7.08,13.022,26]hexacosa-1(25),8(13),9,11,19(26),20,23-heptaene-16,1’-cyclopropane]-18-one	1812770: Inhibition of ROS1 (unknown origin) incubated for 120 mins in presence of 33P-ATP	ic50	0.0002	uM
Entrectinib	1878096: Inhibition of ROS1 (unknown origin)	ic50	0.0002	uM
(4R,12R)-9-fluoro-4,12-dimethyl-5-oxa-3,13,17,18,21-pentazapentacyclo[12.5.2.14,7.06,11.017,20]docosa-1(20),7,9,14(21),15,18-hexaen-2-one	2131664: Inhibition of recombinant human ROS1 G2032R mutant preincubated for 5 to 10 mins followed by substrate and ATP addition and measured after 60 mins by TR-FRET assay	ic50	0.0003	uM
1-[4-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]-3-methoxyphenyl]-3-[2-(dimethylamino)ethyl]imidazolidin-2-one	1550974: Inhibition of N-terminal GST-tagged human ROS1 cytoplasmic domain (1883 to 2347 residues) expressed in Baculovirus expression system using IRS1 as substrate incubated for 1 hr by mobility shift assay	ic50	0.0004	uM
Ceritinib	1419623: Inhibition of ROS1 L2026M mutant (unknown origin)	ki	0.0004	uM
3-(5,5-dimethyl-2H-1,2,4-oxadiazol-3-yl)-N-[(1R)-1-(5-fluoro-2-methoxyphenyl)ethyl]pyrazolo[1,5-a]pyrimidin-5-amine	2131667: Inhibition of human ROS1 using KKKSPGEYVNIEFG as substrate incubated for 120 mins in presence of [gamma-33P]-ATP	ic50	0.0005	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	624899: Binding constant for ROS1 kinase domain	kd	0.0005	uM
N-[(1R)-1-(2-ethoxy-5-fluorophenyl)ethyl]-3-(5-methyl-2,5-dihydro-1,2,4-oxadiazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine	2131667: Inhibition of human ROS1 using KKKSPGEYVNIEFG as substrate incubated for 120 mins in presence of [gamma-33P]-ATP	ic50	0.0005	uM
N-[(1R)-1-(5-fluoro-2-propan-2-yloxyphenyl)ethyl]-3-(5-methyl-2,5-dihydro-1,2,4-oxadiazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-amine	2131667: Inhibition of human ROS1 using KKKSPGEYVNIEFG as substrate incubated for 120 mins in presence of [gamma-33P]-ATP	ic50	0.0005	uM
Crizotinib	1419622: Inhibition of wild type ROS1 (unknown origin)	ki	0.0006	uM
N-[4-[[4-(2-acetamidoanilino)-5-chloropyrimidin-2-yl]amino]-3-methoxyphenyl]morpholine-4-carboxamide	1601319: Inhibition of recombinant human N-terminal GST-tagged ROS (1883 to 2347 residues) cytoplasmic domain expressed in baculovirus expression system using IRS1 as substrate incubated for 1 hr by mobility shift assay	ic50	0.0007	uM
(19R)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,9,10,11,23-hexazapentacyclo[19.3.1.02,6.08,12.013,18]pentacosa-1(25),2(6),4,8,11,13(18),14,16,21,23-decaen-22-amine	2121721: Inhibition of wild type ROS1 (unknown origin)	ic50	0.0007	uM
1-[4-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]-3-methoxyphenyl]-3-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]imidazolidin-2-one	1550974: Inhibition of N-terminal GST-tagged human ROS1 cytoplasmic domain (1883 to 2347 residues) expressed in Baculovirus expression system using IRS1 as substrate incubated for 1 hr by mobility shift assay	ic50	0.0008	uM
2-[3-[4-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]-3-methoxyphenyl]-2-oxoimidazolidin-1-yl]acetamide	1550974: Inhibition of N-terminal GST-tagged human ROS1 cytoplasmic domain (1883 to 2347 residues) expressed in Baculovirus expression system using IRS1 as substrate incubated for 1 hr by mobility shift assay	ic50	0.0008	uM
N-[4-[[4-(2-acetamidoanilino)-5-chloropyrimidin-2-yl]amino]-3-methoxyphenyl]pyrrolidine-1-carboxamide	1601319: Inhibition of recombinant human N-terminal GST-tagged ROS (1883 to 2347 residues) cytoplasmic domain expressed in baculovirus expression system using IRS1 as substrate incubated for 1 hr by mobility shift assay	ic50	0.0010	uM
2-[3-[4-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]-3-methoxyphenyl]-2-oxoimidazolidin-1-yl]-N,N-dimethylacetamide	1550974: Inhibition of N-terminal GST-tagged human ROS1 cytoplasmic domain (1883 to 2347 residues) expressed in Baculovirus expression system using IRS1 as substrate incubated for 1 hr by mobility shift assay	ic50	0.0010	uM
(7S)-10-fluorospiro[5,14-dioxa-2,12,17,21,22,25-hexazapentacyclo[17.5.2.02,7.08,13.022,26]hexacosa-1(25),8(13),9,11,19(26),20,23-heptaene-16,1’-cyclopropane]-18-one	1812770: Inhibition of ROS1 (unknown origin) incubated for 120 mins in presence of 33P-ATP	ic50	0.0010	uM
N-[5-amino-1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]-5-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-2-methylbenzamide	578741: inhibition of ROS	ic50	0.0010	uM
N-[5-(3-fluorophenyl)sulfonyl-2H-pyrazolo[3,4-b]pyridin-3-yl]-4-(4-methylpiperazin-1-yl)benzamide	2131651: Inhibition of ROS1 (unknown origin)	ic50	0.0010	uM
(6R,15R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7(12),8,10,18(25),19,22-heptaen-17-one	1812770: Inhibition of ROS1 (unknown origin) incubated for 120 mins in presence of 33P-ATP	ic50	0.0011	uM
5-chloro-2-N-[2-methoxy-4-[4-[(4-methylpiperazin-1-yl)methyl]triazol-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	1504751: Inhibition of recombinant human N-terminal GST-tagged ROS1 cytoplasmic domain (1883 to 2347 residues) expressed in baculovirus expression system using peptide substrate after 1 hr by mobility shift assay	ic50	0.0011	uM
(7S)-10-fluorospiro[14-oxa-2,5,12,17,21,22,25-heptazapentacyclo[17.5.2.02,7.08,13.022,26]hexacosa-1(25),8(13),9,11,19(26),20,23-heptaene-16,1’-cyclopropane]-18-one	1812770: Inhibition of ROS1 (unknown origin) incubated for 120 mins in presence of 33P-ATP	ic50	0.0012	uM
1-[2-[3-[4-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]-3-methoxyphenyl]-2-oxoimidazolidin-1-yl]acetyl]piperidin-4-one	1550974: Inhibition of N-terminal GST-tagged human ROS1 cytoplasmic domain (1883 to 2347 residues) expressed in Baculovirus expression system using IRS1 as substrate incubated for 1 hr by mobility shift assay	ic50	0.0017	uM
N-[4-[[4-(2-acetamidoanilino)-5-chloropyrimidin-2-yl]amino]-3-methoxyphenyl]-4-(2-hydroxyethyl)piperazine-1-carboxamide	1601319: Inhibition of recombinant human N-terminal GST-tagged ROS (1883 to 2347 residues) cytoplasmic domain expressed in baculovirus expression system using IRS1 as substrate incubated for 1 hr by mobility shift assay	ic50	0.0017	uM
2-[3-(3-hydroxy-5-methylphenyl)-4-[6-[[(2S)-2-hydroxypropyl]amino]-2-pyridin-3-ylpyrimidin-4-yl]pyrazol-1-yl]acetonitrile	1191200: Inhibition of ROS1 (unknown origin) incubated for 20 mins followed by [33P]ATP addition measured after 120 mins by HotSpot assay	ic50	0.0017	uM
5-chloro-2-N-[(E)-(4-fluorophenyl)methylideneamino]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	1330638: Inhibition of ROS1 (unknown origin) using peptide as substrate after 60 mins by HTRF assay	ic50	0.0018	uM
2-[4-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]-3-methoxyphenyl]sulfonyl-1-(4-ethylpiperazin-1-yl)ethanone	1678045: Inhibition of ROS1 (unknown origin) using peptide substrate incubated for 60 mins in presence of ATP by HTRF assay	ic50	0.0019	uM
5-chloro-2-N-[4-[4-(dimethylamino)piperidin-1-yl]-2-methoxyphenyl]-4-N-(2-dimethylphosphorylphenyl)pyrimidine-2,4-diamine	1191196: Inhibition of ROS1 (unknown origin)	ic50	0.0019	uM
Brigatinib	1310833: Inhibition of human ROS1 using KKKSPGEYVNIEFG as substrate and [gamma-33P]ATP measured after 1 hr	ic50	0.0019	uM
(3R,11S)-6-fluoro-11-(fluoromethyl)-3-methyl-10-oxa-2,13,17,18,21-pentazatetracyclo[13.5.2.04,9.018,22]docosa-1(21),4(9),5,7,15(22),16,19-heptaen-14-one	2131654: Inhibition of wild type ROS1 (unknown origin) expressed in BaF3 cells incubated for 4 hrs	ic50	0.0020	uM
N-[5-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methylamino]-4-methoxyphenyl]prop-2-enamide	1584374: Inhibition of recombinant GST-tagged human ROS1 cytoplasmic domain expressed in baculovirus expression system by Z-LYTE assay	ic50	0.0020	uM
5-chloro-2-N-[(E)-(4-methoxyphenyl)methylideneamino]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	1330638: Inhibition of ROS1 (unknown origin) using peptide as substrate after 60 mins by HTRF assay	ic50	0.0023	uM
4-[6-amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridinyl]-1-[2-(dimethylamino)ethyl]pyridin-2-one	1610129: Inhibition of recombinant human N-terminal GST-tagged ROS (1883 to 2347 residues) expressed in baculovirus expression system using IRS1 as substrate incubated with enzyme and substrate for 5 mins followed by ATP addition followed by further incubation for 30 mins by HTRF assay	ic50	0.0023	uM
N-[2-[[5-chloro-2-[4-[[5-[(dimethylamino)methyl]furan-2-yl]methylsulfanyl]-2-methoxyanilino]pyrimidin-4-yl]amino]phenyl]methanesulfonamide	1731978: Inhibition of recombinant human N-terminal GST-tagged ROS1 (1883 to 2347 residues) expressed in baculovirus expression system using IRS1 as substrate incubated for 1 hr by mobility shift assay	ic50	0.0023	uM
5-chloro-2-N-[(E)-1-(4-fluorophenyl)ethylideneamino]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	1330638: Inhibition of ROS1 (unknown origin) using peptide as substrate after 60 mins by HTRF assay	ic50	0.0027	uM
5-chloro-2-N-[4-[4-[[(3S,5R)-3,5-dimethylpiperazin-1-yl]methyl]triazol-1-yl]-2-methoxyphenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	1504751: Inhibition of recombinant human N-terminal GST-tagged ROS1 cytoplasmic domain (1883 to 2347 residues) expressed in baculovirus expression system using peptide substrate after 1 hr by mobility shift assay	ic50	0.0030	uM
N-[4-[[4-(2-acetamidoanilino)-5-chloropyrimidin-2-yl]amino]-3-methoxyphenyl]cyclopropanecarboxamide	1601319: Inhibition of recombinant human N-terminal GST-tagged ROS (1883 to 2347 residues) cytoplasmic domain expressed in baculovirus expression system using IRS1 as substrate incubated for 1 hr by mobility shift assay	ic50	0.0032	uM
5-chloro-4-N-(2-propan-2-ylsulfonylphenyl)-2-N-[(E)-[4-(trifluoromethyl)phenyl]methylideneamino]pyrimidine-2,4-diamine	1330638: Inhibition of ROS1 (unknown origin) using peptide as substrate after 60 mins by HTRF assay	ic50	0.0034	uM
N-[2-[[5-chloro-2-[2-methoxy-4-[2-[(4-methylpiperazin-1-yl)methyl]pyrrol-1-yl]anilino]pyrimidin-4-yl]amino]phenyl]methanesulfonamide	2131650: Inhibition of ROS1 (unknown origin) incubated for 1 hr by HTRF assay	ic50	0.0036	uM
N-[2-[[5-chloro-2-[2-methoxy-4-[(4-oxocyclohexyl)carbamoylamino]anilino]pyrimidin-4-yl]amino]phenyl]acetamide	1601319: Inhibition of recombinant human N-terminal GST-tagged ROS (1883 to 2347 residues) cytoplasmic domain expressed in baculovirus expression system using IRS1 as substrate incubated for 1 hr by mobility shift assay	ic50	0.0037	uM
N-[2-[[5-chloro-2-[2-methoxy-4-(oxolan-2-ylmethoxy)anilino]pyrimidin-4-yl]amino]phenyl]methanesulfonamide	1731978: Inhibition of recombinant human N-terminal GST-tagged ROS1 (1883 to 2347 residues) expressed in baculovirus expression system using IRS1 as substrate incubated for 1 hr by mobility shift assay	ic50	0.0037	uM
N-[2-[[5-chloro-2-[2-methoxy-4-[[5-(pyrrolidin-1-ylmethyl)furan-2-yl]methylsulfanyl]anilino]pyrimidin-4-yl]amino]phenyl]methanesulfonamide	1731978: Inhibition of recombinant human N-terminal GST-tagged ROS1 (1883 to 2347 residues) expressed in baculovirus expression system using IRS1 as substrate incubated for 1 hr by mobility shift assay	ic50	0.0042	uM
N-[2-[[5-chloro-2-[2-methoxy-4-(2-oxopyrrolidin-1-yl)anilino]pyrimidin-4-yl]amino]phenyl]acetamide	1601319: Inhibition of recombinant human N-terminal GST-tagged ROS (1883 to 2347 residues) cytoplasmic domain expressed in baculovirus expression system using IRS1 as substrate incubated for 1 hr by mobility shift assay	ic50	0.0044	uM
5-chloro-2-N-[2-methoxy-4-[4-[(4-methylpiperidin-1-yl)methyl]triazol-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	1504751: Inhibition of recombinant human N-terminal GST-tagged ROS1 cytoplasmic domain (1883 to 2347 residues) expressed in baculovirus expression system using peptide substrate after 1 hr by mobility shift assay	ic50	0.0046	uM

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	4
sodium arsenite	decreases expression	2
(+)-JQ1 compound	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
lorlatinib	affects binding, decreases activity	1
benzo(e)pyrene	decreases methylation	1
cupric chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
obeticholic acid	increases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Decitabine	decreases methylation, increases expression	1
Arsenic Trioxide	affects response to substance	1
Acetaminophen	decreases expression	1
Cadmium	increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Dactinomycin	increases expression	1
Drugs, Chinese Herbal	increases expression	1
Estradiol	affects cotreatment, increases expression	1
Lipopolysaccharides	affects response to substance, affects cotreatment, increases expression	1
Methapyrilene	decreases methylation	1
Tetrachlorodibenzodioxin	decreases expression	1
Thiram	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	decreases expression	1
Particulate Matter	decreases expression	1

ChEMBL screening assays

461 unique, capped per target: 459 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4674748	Binding	Potency index, ratio of IC50 for crizotinib to lorlatinib IC50 for SLC34A2-ROS1 (unknown origin) expressed in human HCC78 cells	Reviving B-Factors: Retrospective Normalized B-Factor Analysis of c-ros Oncogene 1 Receptor Tyrosine Kinase and Anaplastic Lymphoma Kinase L1196M with Crizotinib and Lorlatinib. — ACS Med Chem Lett
CHEMBL1963751	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: ROS1	PubChem BioAssay data set

Cellosaurus cell lines

37 cell lines: 35 cancer cell line, 2 factor-dependent cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_2061	HCC78	Cancer cell line	Male
CVCL_B8NX	Abcam HCT 116 ROS1 KO	Cancer cell line	Male
CVCL_B9B8	Abcam MCF-7 ROS1 KO	Cancer cell line	Female
CVCL_B9R9	Abcam A-549 ROS1 KO	Cancer cell line	Male
CVCL_C8SZ	CUTO-23	Cancer cell line
CVCL_C8T0	CUTO-33	Cancer cell line	Female
CVCL_C8T1	CUTO-27	Cancer cell line
CVCL_C8T2	CUTO-28	Cancer cell line
CVCL_C8T3	CUTO-37	Cancer cell line
CVCL_C8T4	CUTO-38	Cancer cell line

Clinical trials (associated diseases)

514 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00014638	PHASE4	COMPLETED	Letrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
NCT00022386	PHASE4	COMPLETED	Epoetin Alfa in Treating Chemotherapy-Related Anemia in Women With Stage I, Stage II, or Stage III Breast Cancer
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00030758	PHASE4	UNKNOWN	Filgrastim or Pegfilgrastim in Preventing Neutropenia in Women Receiving Chemotherapy Following Surgery for Breast Cancer
NCT00082277	PHASE4	COMPLETED	Anastrozole Biphosphonate Study in Postmenopausal Women With Hormone-Receptor-Positive Early Breast Cancer
NCT00087620	PHASE4	TERMINATED	A Study of Capecitabine In Combination With Docetaxel vs Capecitabine Followed by Docetaxel As First-Line Treatment For Metastatic Breast Cancer
NCT00121836	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) in Women With HER2-Negative Metastatic Breast Cancer
NCT00126360	PHASE4	UNKNOWN	STARS Breast Trial (Study of Anastrozole and Radiotherapy Sequencing Pilot)
NCT00127933	PHASE4	COMPLETED	XeNA Study - A Study of Xeloda (Capecitabine) in Patients With Invasive Breast Cancer
NCT00128297	PHASE4	COMPLETED	Pamidronate Administration in Breast Cancer Patients With Bone Metastases
NCT00129597	PHASE4	UNKNOWN	Effect of Ketalar to Prevent Postoperative Chronic Pain After Mastectomy
NCT00131170	PHASE4	COMPLETED	Paravertebral Block for Breast Surgery
NCT00156039	PHASE4	COMPLETED	Randomized Trial of Follow-up Strategies in Breast Cancer
NCT00160901	PHASE4	COMPLETED	Complementary Therapies for the Reduction of Side Effects During Chemotherapy for Breast Cancer
NCT00171847	PHASE4	TERMINATED	Study of the Efficacy and Safety of Letrozole Combined With Trastuzumab in Patients With Metastatic Breast Cancer
NCT00176046	PHASE4	COMPLETED	Mistletoe Extract in Early or Advanced Breast Cancer, A Feasibility Study
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00234195	PHASE4	COMPLETED	Wellbutrin XL, Major Depressive Disorder and Breast Cancer
NCT00237133	PHASE4	COMPLETED	Treatment of Locally Advanced Breast Cancer With Letrozole in Postmenopausal Women
NCT00237224	PHASE4	COMPLETED	Open Label Study of Postmenopausal Women With ER and /or PgR Positive Breast Cancer Treated With Letrozole
NCT00241046	PHASE4	TERMINATED	Letrozole in the Treatment of 1st and 2nd Line Hormone Receptor Positive Breast Cancer: Pre-therapeutic Risk Assessment
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00323479	PHASE4	COMPLETED	Arthralgia During Anastrozole Therapy for Breast Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00356148	PHASE4	COMPLETED	The Efficacy of Prophylactic Antibiotic Administration During Breast Cancer Surgery in Overweight Patients.
NCT00372476	PHASE4	COMPLETED	Efficacy and Safety of Imatinib and Vinorelbine in Patients With Advanced Breast Cancer
NCT00413491	PHASE4	UNKNOWN	National Screening in Denmark With MR Versus Mammography and Ultrasound of Women With BRCA1 or BRCA2 Mutations
NCT00484614	PHASE4	UNKNOWN	Study the Role of Positron Emission Mammography in Pre-surgical Planning for Breast Cancer
NCT00485953	PHASE4	COMPLETED	Effect of Bisphosphonate on Bone Loss in Postmenopausal Women With Breast Cancer Initiating Aromatase Inhibitor Therapy
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00531973	PHASE4	UNKNOWN	A Study of Liposomal Doxorubicin in Women With Breast Cancer Exploiting Tissue Doppler Imaging
NCT00537771	PHASE4	COMPLETED	Liver Safety Under Upfront Arimidex vs Tamoxifen
NCT00544986	PHASE4	COMPLETED	A Prospective,Open-label Study of Anastrozole in Post-menopausal Women With Hormone Sensitive Advanced Breast Cancer
NCT00613275	PHASE4	COMPLETED	Patient Navigation in the Safety Net:CONNECTeDD
NCT00638599	PHASE4	COMPLETED	Comparison of Laryngeal Mask Airway (LMA®) and Tracheal Tube in Modified Radical Mastectomy on Breast Cancer
NCT00647075	PHASE4	UNKNOWN	Yunzhi as Dietary Supplement in Breast Cancer
NCT00688909	PHASE4	COMPLETED	Rheumatological Evaluation of Anastrozole and Letrozole as Adjuvant Treatment in Post-menopausal Women With Breast Cancer
NCT00699101	PHASE4	TERMINATED	Using the Conture® Multi-Lumen Balloon to Deliver Accelerated Partial Breast Brachytherapy
NCT00742222	PHASE4	COMPLETED	Electronic Xoft Intersociety Brachytherapy Trial: Electronic Brachytherapy (EBT) For Treatment of Early Stage Breast Cancer
NCT00754767	PHASE4	TERMINATED	L-Carnitine L-Tartrate in Preventing Peripheral Neuropathy Caused By Chemotherapy in Women With Metastatic Breast Cancer