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ATM serine/threonine kinase

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Target id: 1934

Nomenclature: ATM serine/threonine kinase

Abbreviated Name: ATM

Family: Other PIKK family kinases

Contents:

Gene and Protein Information Click here for help
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 Click here for help
A-T mutated homolog | ATC | ATD | ATDC | TEL1 | ataxia telangiectasia mutated
Database Links Click here for help
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 Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Human ATM kinase domain with bound M4076 inhibitor
PDB Id:  7NI4
Ligand:  lartesertib
Resolution:  3.0Å
Species:  Human
References:  12
Enzyme Reaction Click here for help
EC Number: 2.7.11.1

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

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
KU-55933 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 8.7 pKi 7
⤷ pKi 8.7 (Ki 2.2x10-9 M) [7]
berzosertib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.5 pKi 3
⤷ pKi 7.5 (Ki 3.4x10-8 M) [3]
AZD1390 Small molecule or natural product Hs Inhibition 10.1 pIC50 2
⤷ pIC50 10.1 (IC50 7.8x10-11 M) [2]
Description: Determined in a cell based assay.
lartesertib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.7 pIC50 4
⤷ pIC50 9.7 (IC50 2x10-10 M) [4]
Description: Inhibition in a biochemical assay, ATP at 10 μM
AZD0156 Small molecule or natural product Primary target of this compound Hs Inhibition 9.2 pIC50 9
⤷ pIC50 9.2 (IC50 5.8x10-10 M) [9]
A011 Small molecule or natural product Hs Inhibition 9.0 pIC50 14
⤷ pIC50 9.0 (IC50 1x10-9 M) [14]
KU-60019 Small molecule or natural product Primary target of this compound Hs Inhibition 8.2 pIC50 6
⤷ pIC50 8.2 (IC50 6.3x10-9 M) [6]
KU-55933 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 7.9 pIC50 7
⤷ pIC50 7.9 (IC50 1.3x10-8 M) [7]
BAY-8400 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 4.7 pIC50 1
⤷ pIC50 4.7 (IC50 1.93x10-5 M) [1]
CP466722 Small molecule or natural product Primary target of this compound Hs Inhibition - - 10
⤷ [10]
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  B cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Immune system development
Immuno Process:  Cellular signalling
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Ataxia-telangiectasia
Disease Ontology: DOID:12704
OMIM: 208900
Orphanet: ORPHA100
Disease:  Ataxia-telangiectasia variant
Orphanet: ORPHA370109
Disease:  Breast cancer
Disease Ontology: DOID:1612
OMIM: 114480
Disease:  Chronic lymphocytic leukemia
Synonyms: B-cell chronic lymphocytic leukemia [Orphanet: ORPHA67038]
Chronic lymphatic leukemia
Chronic lymphoid leukemia
Disease Ontology: DOID:1040
OMIM: 151400
Orphanet: ORPHA67038
Disease:  Combined cervical dystonia
Orphanet: ORPHA370114
Disease:  Mantle cell lymphoma
Description: MCL is an aggressive form of non-Hodgkin’s lymphoma (NHL; median survival of 3-4 years) that arises from B-cells originating within the mantle zone of lymphatic follicles. In the US, around six percent of all new NHL cases are MCL.
Disease Ontology: DOID:0050746
Orphanet: ORPHA52416
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].

References

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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

How to cite this page

Other PIKK family kinases: ATM serine/threonine kinase. Last modified on 26/06/2023. Accessed on 23/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1934.