mitogen-activated protein kinase kinase kinase 5 | STE11 family | IUPHAR/BPS Guide to PHARMACOLOGY

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mitogen-activated protein kinase kinase kinase 5

target has curated data in GtoImmuPdb

Target id: 2080

Nomenclature: mitogen-activated protein kinase kinase kinase 5

Abbreviated Name: ASK1

Family: STE11 family

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1374 6q22.33 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
apoptosis signal regulating kinase 1 | ASK1 | MAPK/ERK kinase kinase 5 | MAPKKK5 | MEK kinase 5
Database Links
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
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:  15
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:  10
Enzyme Reaction
EC Number: 2.7.11.25

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
Ligand Sp. Action Value Parameter Reference
GS-444217 Hs Inhibition 8.5 pIC50 16
pIC50 8.5 (IC50 2.9x10-9 M) [16]
Description: Determined in a TR-FRET immunoassay.
selonsertib Hs Inhibition 8.5 pIC50 12
pIC50 8.5 (IC50 3.2x10-9 M) [12]
Description: Determined is aTR-FRET immunoassay, measuring phosphorylation of a biotinylated peptide substrate by ASK1 kinase.
compound 10 [PMID: 23147077] Hs Inhibition 8.0 pIC50 15
pIC50 8.0 (IC50 1x10-8 M) [15]
MSC2032964A Hs Inhibition 7.0 pIC50 8
pIC50 7.0 (IC50 9.3x10-8 M) [8]
Inhibitor Comments
GS-444217 exhibits >50-fold greater affinity for ASK1 compared with all other kinases tested [16].
DiscoveRx KINOMEscan® screen
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: 4,18

Key to terms and symbols Click column headers to sort
Target used in screen: ASK1
Ligand Sp. Type Action Value Parameter
lestaurtinib Hs Inhibitor Inhibition 7.2 pKd
staurosporine Hs Inhibitor Inhibition 7.0 pKd
erlotinib Hs Inhibitor Inhibition <5.5 pKd
GSK690693 Hs Inhibitor Inhibition <5.5 pKd
ruboxistaurin Hs Inhibitor Inhibition <5.5 pKd
SB203580 Hs Inhibitor Inhibition <5.5 pKd
masitinib Hs Inhibitor Inhibition <5.5 pKd
A-674563 Hs Inhibitor Inhibition <5.5 pKd
gefitinib Hs Inhibitor Inhibition <5.5 pKd
linifanib 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
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: 1,6

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 Hs Inhibitor Inhibition 1.1 1.0 -1.0
K-252a Hs Inhibitor Inhibition 3.6 0.0 0.0
staurosporine Hs Inhibitor Inhibition 4.7 1.5 -1.0
SP600125 Hs Inhibitor Inhibition 47.8 36.0 5.0
Gö 6976 Hs Inhibitor Inhibition 49.8 17.0 16.0
Syk inhibitor Hs Inhibitor Inhibition 53.2 29.0 7.0
SB 218078 Hs Inhibitor Inhibition 56.2 96.0 60.0
PKR inhibitor Hs Inhibitor Inhibition 61.5 26.0 7.0
IKK-2 inhibitor IV Hs Inhibitor Inhibition 75.6 48.0 8.0
indirubin-3'-monoxime 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 GToImmuP as it is a molecular target for anti-fibrotic drug development. This kinase acts upstream of p38 MAPK and JNK kinases [9], and its activation can drive pulmonary and cardiac fibrotic processes [2]. The ASK1>JNK/p38 pathway is also implicated in renal fibrosis [7,13,16].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0045087 innate immune response IEA
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0071356 cellular response to tumor necrosis factor IEA
Physiological Consequences of Altering Gene Expression
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:  11
General Comments
ASK1 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. It sustains TNF- and ROS-induced activations of JNK/p38 and apoptosis [17], and is an anti-fibrosis/anti-inflammatory drug target [5,11,13-14].

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. 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]

5. 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]

6. 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]

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

8. 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]

9. 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]

10. 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]

11. 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]

12. 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.

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

18. 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 17/07/2019. Accessed on 23/11/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2080.