Target Information
| Target General Information | Top | |||||
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| Target ID |
T87871
(Former ID: TTDI01510)
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| Target Name |
Neurotrophic tyrosine kinase ROR1 (ROR1)
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| Synonyms |
receptor tyrosine kinase-like orphan receptor 1; receptor tyrosine kinase like orphan receptor 1; neurotrophic tyrosine kinase, receptor-related 1; dJ537F10.1; Tyrosine-protein kinase transmembrane receptor ROR1; NTRKR1; Inactive tyrosine-protein kinase transmembrane receptor ROR1
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| Gene Name |
ROR1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Diffuse large B-cell lymphoma [ICD-11: 2A81] | |||||
| Function |
Receptor for ligand WNT5A which activate downstream NFkB signaling pathway and may result in the inhibition of WNT3A-mediated signaling. In inner ear, crucial for spiral ganglion neurons to innervate auditory hair cells. Has very low kinase activity in vitro and is unlikely to function as a tyrosine kinase in vivo.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| Sequence |
MHRPRRRGTRPPLLALLAALLLAARGAAAQETELSVSAELVPTSSWNISSELNKDSYLTL
DEPMNNITTSLGQTAELHCKVSGNPPPTIRWFKNDAPVVQEPRRLSFRSTIYGSRLRIRN LDTTDTGYFQCVATNGKEVVSSTGVLFVKFGPPPTASPGYSDEYEEDGFCQPYRGIACAR FIGNRTVYMESLHMQGEIENQITAAFTMIGTSSHLSDKCSQFAIPSLCHYAFPYCDETSS VPKPRDLCRDECEILENVLCQTEYIFARSNPMILMRLKLPNCEDLPQPESPEAANCIRIG IPMADPINKNHKCYNSTGVDYRGTVSVTKSGRQCQPWNSQYPHTHTFTALRFPELNGGHS YCRNPGNQKEAPWCFTLDENFKSDLCDIPACDSKDSKEKNKMEILYILVPSVAIPLAIAL LFFFICVCRNNQKSSSAPVQRQPKHVRGQNVEMSMLNAYKPKSKAKELPLSAVRFMEELG ECAFGKIYKGHLYLPGMDHAQLVAIKTLKDYNNPQQWTEFQQEASLMAELHHPNIVCLLG AVTQEQPVCMLFEYINQGDLHEFLIMRSPHSDVGCSSDEDGTVKSSLDHGDFLHIAIQIA AGMEYLSSHFFVHKDLAARNILIGEQLHVKISDLGLSREIYSADYYRVQSKSLLPIRWMP PEAIMYGKFSSDSDIWSFGVVLWEIFSFGLQPYYGFSNQEVIEMVRKRQLLPCSEDCPPR MYSLMTECWNEIPSRRPRFKDIHVRLRSWEGLSSHTSSTTPSGGNATTQTTSLSASPVSN LSNPRYPNYMFPSQGITPQGQIAGFIGPPIPQNQRFIPINGYPIPPGYAAFPAAHYQPTG PPRVIQHCPPPKSRSPSSASGSTSTGHVTSLPSSGSNQEANIPLLPHMSIPNHPGGMGIT VFGNKSQKPYKIDSKQASLLGDANIHGHTESMISAEL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 7 Clinical Trial Drugs | + | ||||
| 1 | Zilovertamab vedotin | Drug Info | Phase 2/3 | Diffuse large B-cell lymphoma | [2] | |
| 2 | Cirmtuzumab | Drug Info | Phase 2 | Chronic lymphocytic leukaemia | [3] | |
| 3 | VLS-101 | Drug Info | Phase 2 | Solid tumour/cancer | [4] | |
| 4 | Zilovertamab | Drug Info | Phase 2 | Mantle cell lymphoma | [5] | |
| 5 | NBE-002 | Drug Info | Phase 1/2 | Solid tumour/cancer | [6] | |
| 6 | ROR1 CAR-specific Autologous T-Lymphocytes | Drug Info | Phase 1 | Acute lymphoblastic leukaemia | [1] | |
| 7 | ROR1R-CAR-T Cell | Drug Info | Phase 1 | leukaemia | [7] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Antagonist | [+] 1 Antagonist drugs | + | ||||
| 1 | Cirmtuzumab | Drug Info | [9], [10] | |||
| CAR-T-Cell-Therapy | [+] 2 CAR-T-Cell-Therapy drugs | + | ||||
| 1 | ROR1 CAR-specific Autologous T-Lymphocytes | Drug Info | [1] | |||
| 2 | ROR1R-CAR-T Cell | Drug Info | [7] | |||
| 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: Ponatinib | Ligand Info | |||||
| Structure Description | The ROR1 Pseudokinase Domain Bound To Ponatinib | PDB:6TU9 | ||||
| Method | X-ray diffraction | Resolution | 1.94 Å | Mutation | No | [14] |
| PDB Sequence |
KPKSKAKELP
469 LSAVRFMEEL479 GECAFGKIYK489 GHLYLPGMDH499 AQLVAIKTLK509 DYNNPQQWME 519 FQQEASLMAE529 LHHPNIVCLL539 GAVTQEQPVC549 MLFEYINQGD559 LHEFLIMRSL 587 DHGDFLHIAI597 QIAAGMEYLS607 SHFFVHKDLA617 ARNILIGEQL627 HVKISDLGLS 637 REIYSADYYR647 SLLPIRWMPP661 EAIMYGKFSS671 DSDIWSFGVV681 LWEIFSFGLQ 691 PYYGFSNQEV701 IEMVRKRQLL711 PCSEDCPPRM721 YSLMTECWNE731 IPSRRPRFKD 741 IHVRLRSW
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LEU479
3.942
ILE487
4.055
ALA504
3.413
ILE505
4.227
LYS506
3.865
GLU523
2.950
LEU526
3.831
MET527
3.419
LEU530
3.774
ILE535
3.887
VAL536
3.411
PHE552
3.424
GLU553
3.252
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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 Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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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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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Wnt signaling pathway | hsa04310 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Degree | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.68E-01 | Radiality | 1.26E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 2.10E+01 | Topological coefficient | 1.00E+00 | Eccentricity | 13 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Wnt signaling pathway | |||||
| References | Top | |||||
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| REF 1 | ClinicalTrials.gov (NCT02706392) Genetically Modified T-Cell Therapy in Treating Patients With Advanced ROR1+ Malignancies | |||||
| REF 2 | ClinicalTrials.gov (NCT05139017) A Phase 2/3 Multicenter, Open-label, Randomized, Active-Control Study of Zilovertamab Vedotin (MK-2140) in Combination With Standard of Care in Participants With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (waveLINE-003). U.S.National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT04501939) Cirmtuzumab Consolidation for Treatment of Patients With Detectable CLL on Venetoclax (Venetoclax). U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT04504916) A Study of VLS-101 in Patients With Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT03088878) A Phase 1b/2 Study of the ROR1-Targeting Monoclonal Antibody, Cirmtuzumab (UC-961), and the Bruton Tyrosine Kinase Inhibitor, Ibrutinib, in Patients With B-Cell Lymphoid Malignancies. U.S.National Institutes of Health. | |||||
| REF 6 | ClinicalTrials.gov (NCT04441099) NBE-002 in Patients With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 7 | ClinicalTrials.gov (NCT02194374) Autologous ROR1R-CAR-T Cells for Chronic Lymphocytic Leukemia (CLL) | |||||
| REF 8 | ROR1 targeting with the antibody-drug conjugate VLS-101 is effective in Richter syndrome patient-derived xenograft mouse models. Blood. 2021 Jun 17;137(24):3365-3377. | |||||
| REF 9 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 10 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 11 | Clinical pipeline report, company report or official report of VelosBio. | |||||
| REF 12 | The Anti-ROR1 Monoclonal Antibody Zilovertamab Inhibits the Proliferation of Ovarian and Endometrial Cancer Cells. Pharmaceutics. 2022 Apr 11;14(4):837. | |||||
| REF 13 | Clinical pipeline report, company report or official report of NBE-Therapeutics. | |||||
| REF 14 | Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases. Mol Cell. 2020 Aug 6;79(3):390-405.e7. | |||||
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