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Target not currently curated in GtoImmuPdb
Target id: 1934
Nomenclature: ATM serine/threonine kinase
Abbreviated Name: ATM
Family: Other PIKK family kinases
Gene and Protein Information  |
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| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | - | 3056 | 11q22.3 | ATM | ATM serine/threonine kinase | |
| Mouse | - | 3066 | 9 29.12 cM | Atm | ataxia telangiectasia mutated | |
| Rat | - | 3064 | 8q24 | Atm | ATM serine/threonine kinase | |
| Previous and Unofficial Names |
| A-T mutated homolog | ATC | ATD | ATDC | TEL1 | ataxia telangiectasia mutated |
| Database Links |
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| Alphafold | Q13315 (Hs), Q62388 (Mm) |
| BRENDA | 2.7.11.1 |
| CATH/Gene3D | 1.10.1070.11, 1.25.10.10 |
| ChEMBL Target | CHEMBL3797 (Hs) |
| Ensembl Gene | ENSG00000149311 (Hs), ENSMUSG00000034218 (Mm), ENSRNOG00000029773 (Rn) |
| Entrez Gene | 472 (Hs), 11920 (Mm), 300711 (Rn) |
| Human Protein Atlas | ENSG00000149311 (Hs) |
| KEGG Enzyme | 2.7.11.1 |
| KEGG Gene | hsa:472 (Hs), mmu:11920 (Mm), rno:300711 (Rn) |
| OMIM | 607585 (Hs) |
| Orphanet | ORPHA121474 (Hs) |
| Pharos | Q13315 (Hs) |
| RefSeq Nucleotide | NM_000051 (Hs), NM_007499 (Mm), NM_001106821 (Rn) |
| RefSeq Protein | NP_000042 (Hs), NP_031525 (Mm), NP_001100291 (Rn) |
| UniProtKB | Q13315 (Hs), Q62388 (Mm) |
| Wikipedia | ATM (Hs) |
| Selected 3D Structures |
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| Enzyme Reaction |
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Download all structure-activity data for this target as a CSV file 
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| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinically-Relevant Mutations and Pathophysiology
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| General Comments |
| Ataxia telangiectasia mutated (ATM) kinase belongs to the phosphatidyl inositol-3-kinase-like (PIKK) family that includes ataxia- and rad3-related (ATR), mammalian target of rapamycin (mTOR), and DNA-dependent protein (DNA-PK) kinase. It is a critical component for sensing DNA double-stranded breaks, and activating the DNA damage response (DDR) pathway. It may also participate in cellular homeostasis and neurodegenerative diseases [8,11]. There is evidence that ATM activity is elevated in post-mortem Huntington's disease brain, which is postulated as a response to disruption of the transcription-coupled DNA repair (TCR) complex by accumulating aberrant huntingtin (HTT) protein within the TCR [5]. Several pharma companies are developing ATM inhibitors. Only AstraZeneca's program has leads in clinical evaluation, AZD0156 (for solid tumours) and brain-penetrant AZD1390 (for glioblastoma). Structure-based design of brain-penetrant ATM inhibitors with improved selectivity over the potentially detrimental autophagy off-target vacuolar protein sorting 34 (Vps34) kinase, based on the Kudos preclinical inhibitor KU-60019 is ongoing [13]. |
1. Berger M, Wortmann L, Buchgraber P, Lücking U, Zitzmann-Kolbe S, Wengner AM, Bader B, Bömer U, Briem H, Eis K et al.. (2021) BAY-8400: A Novel Potent and Selective DNA-PK Inhibitor which Shows Synergistic Efficacy in Combination with Targeted Alpha Therapies. J Med Chem, 64 (17): 12723-12737. [PMID:34428039]
2. Durant ST, Zheng L, Wang Y, Chen K, Zhang L, Zhang T, Yang Z, Riches L, Trinidad AG, Fok JHL et al.. (2018) The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models. Sci Adv, 4 (6): eaat1719. [PMID:29938225]
3. Fokas E, Prevo R, Pollard JR, Reaper PM, Charlton PA, Cornelissen B, Vallis KA, Hammond EM, Olcina MM, Gillies McKenna W et al.. (2012) Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis, 3: e441. [PMID:23222511]
4. Fuchas T, Becker A, Kubas H, Graedler U. (2020) Imidazolonylquinoline compounds and therapeutic uses thereof. Patent number: WO2020193660A1. Assignee: Merck Patent Gmbh. Priority date: 25/03/2020. Publication date: 01/10/2020.
5. Gao R, Chakraborty A, Geater C, Pradhan S, Gordon KL, Snowden J, Yuan S, Dickey AS, Choudhary S, Ashizawa T et al.. (2019) Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription. Elife, 8. [PMID:30994454]
6. Golding SE, Rosenberg E, Valerie N, Hussaini I, Frigerio M, Cockcroft XF, Chong WY, Hummersone M, Rigoreau L, Menear KA et al.. (2009) Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion. Mol Cancer Ther, 8 (10): 2894-902. [PMID:19808981]
7. Hickson I, Zhao Y, Richardson CJ, Green SJ, Martin NM, Orr AI, Reaper PM, Jackson SP, Curtin NJ, Smith GC. (2004) Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res, 64 (24): 9152-9. [PMID:15604286]
8. Lu XH, Mattis VB, Wang N, Al-Ramahi I, van den Berg N, Fratantoni SA, Waldvogel H, Greiner E, Osmand A, Elzein K et al.. (2014) Targeting ATM ameliorates mutant Huntingtin toxicity in cell and animal models of Huntington's disease. Sci Transl Med, 6 (268): 268ra178. [PMID:25540325]
9. Pike KG, Barlaam B, Cadogan E, Campbell A, Chen Y, Colclough N, Davies NL, de-Almeida C, Degorce SL, Didelot M et al.. (2018) The Identification of Potent, Selective, and Orally Available Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase: The Discovery of AZD0156 (8-{6-[3-(Dimethylamino)propoxy]pyridin-3-yl}-3-methyl-1-(tetrahydro-2 H-pyran-4-yl)-1,3-dihydro-2 H-imidazo[4,5- c]quinolin-2-one). J Med Chem, 61 (9): 3823-3841. [PMID:29683659]
10. Rainey MD, Charlton ME, Stanton RV, Kastan MB. (2008) Transient inhibition of ATM kinase is sufficient to enhance cellular sensitivity to ionizing radiation. Cancer Res, 68 (18): 7466-74. [PMID:18794134]
11. Shiloh Y, Ziv Y. (2013) The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol, 14 (4): 197-210. [PMID:23847781]
12. Stakyte K, Rotheneder M, Lammens K, Bartho JD, Grädler U, Fuchß T, Pehl U, Alt A, van de Logt E, Hopfner KP. (2021) Molecular basis of human ATM kinase inhibition. Nat Struct Mol Biol, 28 (10): 789-798. [PMID:34556870]
13. Van de Poël A, Toledo-Sherman L, Breccia P, Cachope R, Bate JR, Angulo-Herrera I, Wishart G, Matthews KL, Martin SL, Peacock M et al.. (2021) Structure-Based Exploration of Selectivity for ATM Inhibitors in Huntington's Disease. J Med Chem, 64 (8): 5018-5036. [PMID:33783225]
14. Zhang S, Zhou P, Liu J, Xia A, Lin G, Xiagn Z, Fang Z, Yang X, Qiao J, Hu Q et al.. (2023) Discovery of [1,2,3]Triazolo[4,5-c]quinoline Derivatives as a New Class of Ataxia-Telangiectasia Mutated Kinase Inhibitors. ACS Med Chem Lett, 14 (6): 746–756 Epub ahead of print. DOI: 10.1021/acsmedchemlett.3c00034
Other PIKK family kinases: ATM serine/threonine kinase. Last modified on 26/06/2023. Accessed on 11/09/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1934.
