Target has curated data in GtoImmuPdb
Contents:
Gene and Protein Information  |
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| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 1 | 2555 | 9q34.3 | NOTCH1 | notch receptor 1 | |
| Mouse | 1 | 2531 | 2 18.91 cM | Notch1 | notch 1 | |
| Rat | 1 | 2531 | 3p13 | Notch1 | notch receptor 1 | |
| Previous and Unofficial Names |
| notch 1 | Notch (Drosophila) homolog 1 (translocation-associated) | TAN1 |
| Database Links |
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| Alphafold | P46531 (Hs), Q01705 (Mm), Q07008 (Rn) |
| CATH/Gene3D | 1.25.40.20 |
| ChEMBL Target | CHEMBL2146346 (Hs), CHEMBL4295799 (Mm) |
| Ensembl Gene | ENSG00000148400 (Hs), ENSMUSG00000026923 (Mm), ENSRNOG00000019322 (Rn) |
| Entrez Gene | 4851 (Hs), 18128 (Mm), 25496 (Rn) |
| Human Protein Atlas | ENSG00000148400 (Hs) |
| KEGG Gene | hsa:4851 (Hs), mmu:18128 (Mm), rno:25496 (Rn) |
| OMIM | 190198 (Hs) |
| Pharos | P46531 (Hs) |
| RefSeq Nucleotide | NM_017617 (Hs), NM_008714 (Mm), NM_001105721 (Rn) |
| RefSeq Protein | NP_060087 (Hs), NP_032740 (Mm), NP_001099191 (Rn) |
| UniProtKB | P46531 (Hs), Q01705 (Mm), Q07008 (Rn) |
| Wikipedia | NOTCH1 (Hs) |
Download all structure-activity data for this target as a CSV file 
| Inhibitors | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||
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| Inhibitor Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||
| CB-103 is a small molecule that binds to the cleaved NOTCH1 receptor intracellular domain (NICD) that translocates to the nucleus and is a component of the functional nuclear NOTCH transcriptional activation complex. By inhibiting NOTCH-mediated transcriptional activation, CB-103 brings about anti-tumour effects in cancer cells that are driven by dominant active NICD. | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Immunopharmacology Comments |
| NOTCH1 and its ligand Delta-like 4 (DLL4) play a dominant role in mediating the effects of Notch signaling in T cells during Graft-versus-host disease (GvHD). Anti-NOTCH1 or anti-DLL4 antibodies controlled GvHD [8]. Anti-NOTCH1 was associated with dose-limiting toxicity; anti-DLL4 was not. Activating mutations in NOTCH1 are one of the most frequent somatic alterations detected in chronic lymphocytic leukemia (CLL), and such mutations are associated with poor prognosis [6-7,9]. The mutations found in CLL generally affect the PEST domain of the receptor, are not ongogenic in isolation and are NOTCH ligand dependent. Different NOTCH1 mutations are found in T-acute lymphoblastic leukemia (T-ALL) [2], and these are more likely to lead to constitutive, ligand-independent NOTCH pathway activation. |
| Immuno Process Associations | ||
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| General Comments |
| NOTCH1 is a single-pass transmembrane receptor protein that controls T-cell differentiation. Gain-of-function mutations in NOTCH1 are present in >50% of human T-cell acute lymphoblastic leukemias (T-ALL) [3-4]. |
References
1. Astudillo L, Da Silva TG, Wang Z, Han X, Jin K, VanWye J, Zhu X, Weaver K, Oashi T, Lopes PE et al.. (2016) The Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis. Cancer Res, 76 (12): 3593-603. [PMID:27197169]
2. Belver L, Ferrando A. (2016) The genetics and mechanisms of T cell acute lymphoblastic leukaemia. Nat Rev Cancer, 16 (8): 494-507. [PMID:27451956]
3. Bhanushali AA, Babu S, Thangapandi VR, Pillai R, Chheda P, Das BR. (2010) Mutations in the HD and PEST domain of Notch-1 receptor in T-cell acute lymphoblastic leukemia: report of novel mutations from Indian population. Oncol Res, 19 (2): 99-104. [PMID:21302811]
4. Grabher C, von Boehmer H, Look AT. (2006) Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat Rev Cancer, 6 (5): 347-59. [PMID:16612405]
5. Gurney Al, Hoey TC, Bruhns MF, Axelrod FT. (2014) Notch1 receptor binding agents and methods of use thereof. Patent number: US20140011271A1. Assignee: Oncomed Pharmaceuticals. Priority date: 08/07/2008. Publication date: 09/01/2014.
6. Puente XS, Pinyol M, Quesada V, Conde L, Ordóñez GR, Villamor N, Escaramis G, Jares P, Beà S, González-Díaz M et al.. (2011) Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature, 475 (7354): 101-5. [PMID:21642962]
7. Rossi D, Rasi S, Fabbri G, Spina V, Fangazio M, Forconi F, Marasca R, Laurenti L, Bruscaggin A, Cerri M et al.. (2012) Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood, 119 (2): 521-9. [PMID:22077063]
8. Tran IT, Sandy AR, Carulli AJ, Ebens C, Chung J, Shan GT, Radojcic V, Friedman A, Gridley T, Shelton A et al.. (2013) Blockade of individual Notch ligands and receptors controls graft-versus-host disease. J Clin Invest, 123 (4): 1590-604. [PMID:23454750]
9. Villamor N, Conde L, Martínez-Trillos A, Cazorla M, Navarro A, Beà S, López C, Colomer D, Pinyol M, Aymerich M et al.. (2013) NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome. Leukemia, 27 (5): 1100-6. [PMID:23295735]
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