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mitogen-activated protein kinase kinase kinase 5

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2080

Nomenclature: mitogen-activated protein kinase kinase kinase 5

Abbreviated Name: ASK1

Family: STE11 family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1374 6q23.3 MAP3K5 mitogen-activated protein kinase kinase kinase 5
Mouse - 1380 10 A3 Map3k5 mitogen-activated protein kinase kinase kinase 5
Rat - - 1p 12 Map3k5 mitogen-activated protein kinase kinase kinase 5
Previous and Unofficial Names Click here for help
apoptosis signal regulating kinase 1 | ASK1 | MAPK/ERK kinase kinase 5 | MAPKKK5 | MEK kinase 5
Database Links Click here for help
Alphafold Q99683 (Hs), O35099 (Mm)
BRENDA 2.7.11.25
ChEMBL Target CHEMBL5285 (Hs), CHEMBL4879411 (Mm)
Ensembl Gene ENSG00000197442 (Hs), ENSMUSG00000071369 (Mm), ENSRNOG00000031700 (Rn)
Entrez Gene 4217 (Hs), 26408 (Mm), 293015 (Rn)
Human Protein Atlas ENSG00000197442 (Hs)
KEGG Enzyme 2.7.11.25
KEGG Gene hsa:4217 (Hs), mmu:26408 (Mm), rno:293015 (Rn)
OMIM 602448 (Hs)
Pharos Q99683 (Hs)
RefSeq Nucleotide NM_005923 (Hs), NM_008580 (Mm)
RefSeq Protein NP_005914 (Hs), NP_032606 (Mm)
SynPHARM 81444 (in complex with compound 10 [PMID: 23147077])
UniProtKB Q99683 (Hs), O35099 (Mm)
Wikipedia MAP3K5 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Structure of mitogen-activated protein kinase kinase kinase 5
PDB Id:  2CLQ
Resolution:  2.3Å
Species:  Human
References:  3
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human apoptosis signal-regulating kinase 1 (ASK1) with imidazopyridine inhibitor
PDB Id:  3VW6
Resolution:  2.4Å
Species:  Human
References:  22
Image of receptor 3D structure from RCSB PDB
Description:  ASK1 kinase domain in complex with inhibitor (GS-444217).
PDB Id:  6E2O
Ligand:  GS-444217
Resolution:  2.4Å
Species:  Human
References:  15
Image of receptor 3D structure from RCSB PDB
Description:  ASK1 kinase domain in complex with GS-4997 (selonsertib).
PDB Id:  6OYT
Ligand:  selonsertib
Resolution:  2.82Å
Species:  Human
References:  11
Enzyme Reaction Click here for help
EC Number: 2.7.11.25

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
GS-444217 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 8.5 pIC50 23
⤷ pIC50 8.5 (IC50 2.9x10-9 M) [23]
Description: Determined in a TR-FRET immunoassay.
selonsertib Small molecule or natural product Primary target of this compound Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.5 pIC50 19
⤷ pIC50 8.5 (IC50 3.2x10-9 M) [19]
Description: Determined is aTR-FRET immunoassay, measuring phosphorylation of a biotinylated peptide substrate by ASK1 kinase.
compound 10 [PMID: 23147077] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.0 pIC50 22
⤷ pIC50 8.0 (IC50 1x10-8 M) [22]
compound 26 [PMID: 31710475] Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 6.8 – 8.2 pIC50 11
⤷ pIC50 8.2 (IC50 6x10-9 M) [11]
Description: Biochemical assay; inhibition of ASK1 autophosphorylation.
pIC50 6.8 (IC50 1.48x10-7 M) [11]
Description: Cellular assay; inhibition of ASK1-T838 autophosphorylation in HEK293T cells.
MSC2032964A Small molecule or natural product Primary target of this compound Hs Inhibition 7.0 pIC50 9
⤷ pIC50 7.0 (IC50 9.3x10-8 M) [9]
Inhibitor Comments
GS-444217 exhibits >50-fold greater affinity for ASK1 compared with all other kinases tested [23].
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 5,25
Key to terms and symbols Click column headers to sort
Target used in screen: ASK1
Ligand Sp. Type Action Value Parameter
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.2 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.0 pKd
erlotinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
GSK690693 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
ruboxistaurin Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
SB203580 Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition <5.5 pKd
masitinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition <5.5 pKd
A-674563 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
linifanib Small molecule or natural product Hs Inhibitor Inhibition <5.5 pKd
gefitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx

Reference: 1,7
Key to terms and symbols Click column headers to sort
Target used in screen: ASK1/ASK1(MAP3K5)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.1 1.0 -1.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 3.6 0.0 0.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 4.7 1.5 -1.0
SP600125 Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 47.8 36.0 5.0
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 49.8 17.0 16.0
Syk inhibitor Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 53.2 29.0 7.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 56.2 96.0 60.0
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 61.5 26.0 7.0
IKK-2 inhibitor IV Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 75.6 48.0 8.0
indirubin-3'-monoxime Small molecule or natural product Hs Inhibitor Inhibition 84.3 52.0 7.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
ASK1 is included in the GToImmuPdb as it is a molecular target for anti-fibrotic drug development. This kinase acts upstream of p38 MAPK and JNK kinases [12], and its activation can drive pulmonary and cardiac fibrotic processes [2,13]. The ASK1>JNK/p38 pathway is also implicated in renal [8,20,23] and liver fibrosis. The most advanced ASK1 inhibitor in clinical development (in January 2020) is Gilead's selonsertib [16], which has been evaluated in patients with nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD). Selonsertib has completed Phase 3 trials as monotherapy, and is also being tested in combination with antisteatotic/antilipemic agents such as firsocostat (allosteric ACC inhibitor), cilofexor (FXR agonist), fenofibrate (PPARα agonist) and icosapent (in Phase 2 trial NCT02781584).
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Cytokine production & signalling
Physiological Consequences of Altering Gene Expression Click here for help
Ask1-/- mice have a normal phenotype and normal kidney structure and function. However, they exhibit dramatically reduced p38 MAPK activation and are protected from kidney injury in models of acute tubular necrosis and renal interstitial fibrosis.
Species:  Mouse
Tissue:  Renal
Technique: 
References:  17
General Comments
Apoptosis signal-regulating kinase 1 (ASK1, MAP3K5) is a stress-activated kinase. It is activated by cytotoxic stress factors such as TNF, Fas and reactive oxygen species (ROS), and once activated (autophosphorylated) it phosphorylates and activates downstream JNK and p38 MAP kinases which are responsible for the inflammatory and apoptotic stress responses [24]. ASK1 is an anti-fibrosis/anti-inflammatory drug target [6,17,20-21]. Modulation of ASK1 activity might also be relevant in the treatment of degenerative neurological disorders (MND [18], MS [9], Parkinson's disease [14], Alzheimer's disease [10] and ischemic stroke [4]) [11].

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1039-45. [PMID:22037377]

2. Budas GR, Boehm M, Kojonazarov B, Viswanathan G, Tian X, Veeroju S, Novoyatleva T, Grimminger F, Hinojosa-Kirschenbaum F, Ghofrani HA et al.. (2018) ASK1 Inhibition Halts Disease Progression in Preclinical Models of Pulmonary Arterial Hypertension. Am J Respir Crit Care Med, 197 (3): 373-385. [PMID:28910144]

3. Bunkoczi G, Salah E, Filippakopoulos P, Fedorov O, Müller S, Sobott F, Parker SA, Zhang H, Min W, Turk BE et al.. (2007) Structural and functional characterization of the human protein kinase ASK1. Structure, 15 (10): 1215-26. [PMID:17937911]

4. Cheon SY, Kim EJ, Kim SY, Kim JM, Kam EH, Park JK, Koo BN. (2018) Apoptosis Signal-regulating Kinase 1 Silencing on Astroglial Inflammasomes in an Experimental Model of Ischemic Stroke. Neuroscience, 390: 218-230. [PMID:30172704]

5. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1046-51. [PMID:22037378]

6. Furuichi K, Wada T, Iwata Y, Sakai N, Yoshimoto K, Kobayashi Ki K, Mukaida N, Matsushima K, Yokoyama H. (2002) Administration of FR167653, a new anti-inflammatory compound, prevents renal ischaemia/reperfusion injury in mice. Nephrol Dial Transplant, 17 (3): 399-407. [PMID:11865084]

7. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem J, 451 (2): 313-28. [PMID:23398362]

8. Grynberg K, Ma FY, Nikolic-Paterson DJ. (2017) The JNK Signaling Pathway in Renal Fibrosis. Front Physiol, 8: 829. [PMID:29114233]

9. Guo X, Harada C, Namekata K, Matsuzawa A, Camps M, Ji H, Swinnen D, Jorand-Lebrun C, Muzerelle M, Vitte PA et al.. (2010) Regulation of the severity of neuroinflammation and demyelination by TLR-ASK1-p38 pathway. EMBO Mol Med, 2 (12): 504-15. [PMID:21064192]

10. Hasegawa Y, Toyama K, Uekawa K, Ichijo H, Kim-Mitsuyama S. (2018) Role of ASK1/p38 Cascade in a Mouse Model of Alzheimer's Disease and Brain Aging. J Alzheimers Dis, 61 (1): 259-263. [PMID:29154282]

11. Himmelbauer MK, Xin Z, Jones JH, Enyedy I, King K, Marcotte DJ, Murugan P, Santoro JC, Hesson T, Spilker K et al.. (2019) Rational Design and Optimization of a Novel Class of Macrocyclic Apoptosis Signal-Regulating Kinase 1 Inhibitors. J Med Chem, 62 (23): 10740-10756. [PMID:31710475]

12. Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y. (1997) Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science, 275 (5296): 90-4. [PMID:8974401]

13. Lanier M, Pickens J, Bigi SV, Bradshaw-Pierce EL, Chambers A, Cheruvallath ZS, Cole D, Dougan DR, Ermolieff J, Gibson T et al.. (2017) Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure. ACS Med Chem Lett, 8 (3): 316-320. [PMID:28337323]

14. Lee KW, Woo JM, Im JY, Park ES, He L, Ichijo H, Junn E, Mouradian MM. (2015) Apoptosis signal-regulating kinase 1 modulates the phenotype of α-synuclein transgenic mice. Neurobiol Aging, 36 (1): 519-26. [PMID:25219466]

15. Liles JT, Corkey BK, Notte GT, Budas GR, Lansdon EB, Hinojosa-Kirschenbaum F, Badal SS, Lee M, Schultz BE, Wise S et al.. (2018) ASK1 contributes to fibrosis and dysfunction in models of kidney disease. J Clin Invest, 128 (10): 4485-4500. [PMID:30024858]

16. Loomba R, Lawitz E, Mantry PS, Jayakumar S, Caldwell SH, Arnold H, Diehl AM, Djedjos CS, Han L, Myers RP et al.. (2018) The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial. Hepatology, 67 (2): 549-559. [PMID:28892558]

17. Ma FY, Tesch GH, Nikolic-Paterson DJ. (2014) ASK1/p38 signaling in renal tubular epithelial cells promotes renal fibrosis in the mouse obstructed kidney. Am J Physiol Renal Physiol, 307 (11): F1263-73. [PMID:25298527]

18. Nishitoh H, Kadowaki H, Nagai A, Maruyama T, Yokota T, Fukutomi H, Noguchi T, Matsuzawa A, Takeda K, Ichijo H. (2008) ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1. Genes Dev, 22 (11): 1451-64. [PMID:18519638]

19. Notte G. (2014) Apoptosis signal-regulating kinase inhibitor. Patent number: US8742126 B2. Assignee: Gilead Sciences, Inc.. Priority date: 27/01/2012. Publication date: 03/06/2014.

20. Stambe C, Atkins RC, Tesch GH, Masaki T, Schreiner GF, Nikolic-Paterson DJ. (2004) The role of p38alpha mitogen-activated protein kinase activation in renal fibrosis. J Am Soc Nephrol, 15 (2): 370-9. [PMID:14747383]

21. Terada Y, Inoshita S, Kuwana H, Kobayashi T, Okado T, Ichijo H, Sasaki S. (2007) Important role of apoptosis signal-regulating kinase 1 in ischemic acute kidney injury. Biochem Biophys Res Commun, 364 (4): 1043-9. [PMID:17971303]

22. Terao Y, Suzuki H, Yoshikawa M, Yashiro H, Takekawa S, Fujitani Y, Okada K, Inoue Y, Yamamoto Y, Nakagawa H et al.. (2012) Design and biological evaluation of imidazo[1,2-a]pyridines as novel and potent ASK1 inhibitors. Bioorg Med Chem Lett, 22 (24): 7326-9. [PMID:23147077]

23. Tesch GH, Ma FY, Han Y, Liles JT, Breckenridge DG, Nikolic-Paterson DJ. (2015) ASK1 Inhibitor Halts Progression of Diabetic Nephropathy in Nos3-Deficient Mice. Diabetes, 64 (11): 3903-13. [PMID:26180085]

24. Tobiume K, Matsuzawa A, Takahashi T, Nishitoh H, Morita K, Takeda K, Minowa O, Miyazono K, Noda T, Ichijo H. (2001) ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Rep, 2 (3): 222-8. [PMID:11266364]

25. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem Biol, 17 (11): 1241-9. [PMID:21095574]

How to cite this page

STE11 family: mitogen-activated protein kinase kinase kinase 5. Last modified on 30/01/2020. Accessed on 17/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2080.