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serine/threonine kinase 3

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Target id: 2219

Nomenclature: serine/threonine kinase 3

Abbreviated Name: MST2

Family: MST subfamily

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 491 8q22.2 STK3 serine/threonine kinase 3
Mouse - 497 15 B3.1 Stk3 serine/threonine kinase 3
Rat - 491 7q22 Stk3 serine/threonine kinase 3
Previous and Unofficial Names Click here for help
KRS1 | mess1
Database Links Click here for help
Alphafold Q13188 (Hs), Q9JI10 (Mm), O54748 (Rn)
BRENDA 2.7.11.1
ChEMBL Target CHEMBL4708 (Hs), CHEMBL4310 (Mm)
Ensembl Gene ENSG00000104375 (Hs), ENSMUSG00000022329 (Mm), ENSRNOG00000011278 (Rn)
Entrez Gene 6788 (Hs), 56274 (Mm), 65189 (Rn)
Human Protein Atlas ENSG00000104375 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:6788 (Hs), mmu:56274 (Mm), rno:65189 (Rn)
OMIM 605030 (Hs)
Pharos Q13188 (Hs)
RefSeq Nucleotide NM_001256312 (Hs), NM_019635 (Mm), NM_031735 (Rn)
RefSeq Protein NP_006272 (Hs), NP_062609 (Mm), NP_113923 (Rn)
UniProtKB Q13188 (Hs), Q9JI10 (Mm), O54748 (Rn)
Wikipedia STK3 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of MST2 in complex with XMU-MP-1
PDB Id:  5DH3
Ligand:  XMU-MP-1
Resolution:  2.47Å
Species:  Human
References:  5
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
staurosporine Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.4 pIC50 7
⤷ pIC50 9.4 (IC50 4.1x10-10 M) [7]
CEP-11981 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.7 pIC50 8
⤷ pIC50 7.7 (IC50 2.1x10-8 M) [8]
SBP-3264 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.4 pIC50 2
⤷ pIC50 7.4 (IC50 3.6x10-8 M) [2]
XMU-MP-1 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.8 pIC50 2
⤷ pIC50 6.8 (IC50 1.62x10-7 M) [2]
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: 3,10
Key to terms and symbols Click column headers to sort
Target used in screen: MST2
Ligand Sp. Type Action Value Parameter
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 9.7 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.6 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.3 pKd
neratinib Small molecule or natural product Approved drug Hs Inhibitor Inhibition 7.2 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 7.2 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 6.8 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.7 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.5 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.4 pKd
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 6.3 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: 1,6
Key to terms and symbols Click column headers to sort
Target used in screen: MST2/MST2(STK3)
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.1 4.5 0.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.3 0.0 1.0
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 1.9 3.0 0.0
JAK3 inhibitor VI Small molecule or natural product Hs Inhibitor Inhibition 2.7 5.0 0.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 2.9 2.0 1.0
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 3.1 2.0 2.0
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 3.2 10.0 12.0
PKR inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 3.4 2.0 1.0
indirubin derivative E804 Small molecule or natural product Hs Inhibitor Inhibition 4.8 4.0 1.0
JAK inhibitor I Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.4 14.0 4.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
The kinases MST1 and MST2 are key components of the Hippo signalling pathway. MST1/2 function has been identified as a signal-dependent amplifier of IL-2−STAT5 signalling in Treg cells that maintains immune tolerance, and to be essential for prevention of tumour resistance and autoimmunity [9]. The Hippo pathway, also appears to couple the cellular metabolic state and immune function of CD8α+ dendritic cells, in a mechanism that progammes this dendritic cell subset to present antigens to, and selectively prime CD8+ T cells [4]. In this way, output from the Hippo signalling pathway is able to induce cytotoxic T cell responses to viruses, bacteria and tumours. Manipulating this selective dendritic cell process has implications for cancer immunotherapy, and for treating immune disorders. It can be envisioned that pharmacological agents could be developed which are able to activate CD8α+ dendritic cells, shape the adaptive immune response, and prime anti-tumour T cells.
Immuno Process Associations
Immuno Process:  Immune system development

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. Bata N, Chaikuad A, Bakas NA, Limpert AS, Lambert LJ, Sheffler DJ, Berger LM, Liu G, Yuan C, Wang L et al.. (2022) Inhibitors of the Hippo Pathway Kinases STK3/MST2 and STK4/MST1 Have Utility for the Treatment of Acute Myeloid Leukemia. J Med Chem, 65 (2): 1352-1369. [PMID:34807584]

3. 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]

4. Du X, Wen J, Wang Y, Karmaus PWF, Khatamian A, Tan H, Li Y, Guy C, Nguyen TM, Dhungana Y et al.. (2018) Hippo/Mst signalling couples metabolic state and immune function of CD8α+ dendritic cells. Nature, 558 (7708): 141-145. [PMID:29849151]

5. Fan F, He Z, Kong LL, Chen Q, Yuan Q, Zhang S, Ye J, Liu H, Sun X, Geng J et al.. (2016) Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration. Sci Transl Med, 8 (352): 352ra108. [PMID:27535619]

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. Hall MD, Salam NK, Hellawell JL, Fales HM, Kensler CB, Ludwig JA, Szakács G, Hibbs DE, Gottesman MM. (2009) Synthesis, activity, and pharmacophore development for isatin-beta-thiosemicarbazones with selective activity toward multidrug-resistant cells. J Med Chem, 52 (10): 3191-204. [PMID:19397322]

8. Hudkins RL, Becknell NC, Zulli AL, Underiner TL, Angeles TS, Aimone LD, Albom MS, Chang H, Miknyoczki SJ, Hunter K et al.. (2012) Synthesis and biological profile of the pan-vascular endothelial growth factor receptor/tyrosine kinase with immunoglobulin and epidermal growth factor-like homology domains 2 (VEGF-R/TIE-2) inhibitor 11-(2-methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (CEP-11981): a novel oncology therapeutic agent. J Med Chem, 55 (2): 903-13. [PMID:22148921]

9. Shi H, Liu C, Tan H, Li Y, Nguyen TM, Dhungana Y, Guy C, Vogel P, Neale G, Rankin S et al.. (2018) Hippo Kinases Mst1 and Mst2 Sense and Amplify IL-2R-STAT5 Signaling in Regulatory T Cells to Establish Stable Regulatory Activity. Immunity, 49 (5): 899-914.e6. [PMID:30413360]

10. 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

MST subfamily: serine/threonine kinase 3. Last modified on 24/11/2021. Accessed on 15/10/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2219.