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Pim-1 proto-oncogene, serine/threonine kinase

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Target id: 2158

Nomenclature: Pim-1 proto-oncogene, serine/threonine kinase

Abbreviated Name: Pim1

Family: PIM family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 313 6p21.2 PIM1 Pim-1 proto-oncogene, serine/threonine kinase
Mouse - 313 17 15.38 cM Pim1 proviral integration site 1
Rat - 313 20p12 Pim1 Pim-1 proto-oncogene, serine/threonine kinase
Previous and Unofficial Names Click here for help
proto-oncogene serine/threonine-protein kinase pim-1 | proviral integration site 1 | pim-1 oncogene | Pim-1 proto-oncogene
Database Links Click here for help
Alphafold P11309 (Hs), P06803 (Mm), P26794 (Rn)
BRENDA 2.7.11.1
ChEMBL Target CHEMBL2147 (Hs), CHEMBL3297640 (Mm)
Ensembl Gene ENSG00000137193 (Hs), ENSMUSG00000024014 (Mm), ENSRNOG00000000529 (Rn)
Entrez Gene 5292 (Hs), 18712 (Mm), 24649 (Rn)
Human Protein Atlas ENSG00000137193 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:5292 (Hs), mmu:18712 (Mm), rno:24649 (Rn)
OMIM 164960 (Hs)
Pharos P11309 (Hs)
RefSeq Nucleotide NM_001243186 (Hs), NM_008842 (Mm), NM_017034 (Rn)
RefSeq Protein NP_002639 (Hs), NP_032868 (Mm), NP_058730 (Rn)
SynPHARM 80328 (in complex with Akt inhibitor X)
81576 (in complex with compound 20 [PMID: 22136433])
85855 (in complex with compound 28 [PMID: 30624936])
83954 (in complex with LGB321)
84813 (in complex with PIM447)
80356 (in complex with ruboxistaurin)
UniProtKB P11309 (Hs), P06803 (Mm), P26794 (Rn)
Wikipedia PIM1 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  The discovery of novel benzofuran-2-carboxylic acids as potent Pim-1 inhibitors
PDB Id:  3R04
Resolution:  1.7Å
Species:  Human
References:  24
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of hPim-1 kinase at 2.1 A resolution
PDB Id:  1XQZ
Resolution:  2.1Å
Species:  Human
References:  20
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human PIM1 in complex with LY-333531 (ruboxistaurin).
PDB Id:  2J2I
Ligand:  ruboxistaurin
Resolution:  1.9Å
Species:  Human
References:  9
Image of receptor 3D structure from RCSB PDB
Description:  Pim1 Complexed with a pyridylcarboxamide
PDB Id:  4N70
Ligand:  LGB321
Resolution:  2.1Å
Species:  Human
References:  3
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of hPIM1 bound to PIM447.
PDB Id:  5DWR
Ligand:  PIM447
Resolution:  2.0Å
Species:  Human
References:  4
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of human Pim-1 kinase in complex with a quinazolinone-pyrrolodihydropyrrolone inhibitor
PDB Id:  6MT0
Ligand:  compound 28 [PMID: 30624936]
Resolution:  2.2Å
Species:  Human
References:  21
Image of receptor 3D structure from RCSB PDB
Description:  PIM1 in complex with Cpd16 (5-amino-N-(5-((4R,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide)
PDB Id: 
Ligand:  GDC-0339
Resolution:  1.71Å
Species:  Human
References:  22
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
LGB321 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 12.0 pKi 12
⤷ pKi 12.0 (Ki 1x10-12 M) [12]
Description: Assayed at 400μM ATP
PIM447 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 11.2 pKi 4
⤷ pKi 11.2 (Ki 6x10-12 M) [4]
AZD1208 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 10.8 pKi 3
⤷ pKi 10.8 (Ki 1.7x10-11 M) [3]
GDC-0339 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 10.5 pKi 22
⤷ pKi 10.5 (Ki 3x10-11 M) [22]
nuvisertib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.3 pKi 10
⤷ pKi 8.3 (Ki 5x10-9 M) [10]
uzansertib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.6 pIC50 15
⤷ pIC50 9.6 (IC50 2.4x10-10 M) [15]
Description: Kinase inhibition in a biochemical enzyme activity assay.
leucettine L41 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.4 pIC50 7
⤷ pIC50 8.4 (IC50 4.1x10-9 M) [7]
compound 14k [PMID: 21982499] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 8.3 pIC50 19
⤷ pIC50 8.3 (IC50 5x10-9 M) [19]
CX-6258 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.3 pIC50 13
⤷ pIC50 8.3 (IC50 5x10-9 M) [13]
SGI-1776 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.1 pIC50 8
⤷ pIC50 8.1 (IC50 7x10-9 M) [8]
XL413 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.4 pIC50 16
⤷ pIC50 7.4 (IC50 4.2x10-8 M) [16]
compound 28 [PMID: 30624936] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.3 pIC50 21
⤷ pIC50 7.3 (IC50 5x10-8 M) [21]
compound 20 [PMID: 22136433] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.2 pIC50 14
⤷ pIC50 7.2 (IC50 6x10-8 M) [14]
voruciclib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.1 pIC50 18
⤷ pIC50 7.1 (IC50 7.2x10-8 M) [18]
ruboxistaurin Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.7 pIC50 9
⤷ pIC50 6.7 (IC50 2x10-7 M) [9]
silmitasertib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.7 pIC50 2
⤷ pIC50 6.7 (IC50 2.16x10-7 M) [2]
compound 2 [PMID: 22560567] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.5 pIC50 16
⤷ pIC50 6.5 (IC50 3.32x10-7 M) [16]
Akt inhibitor X Small molecule or natural product Ligand has a PDB structure Hs Inhibition 5.9 pIC50 17
⤷ pIC50 5.9 (IC50 1.28x10-6 M) [17]
CX-5011 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.6 pIC50 2
⤷ pIC50 5.6 (IC50 2.51x10-6 M) [2]
CX-5279 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.1 pIC50 2
⤷ pIC50 5.1 (IC50 8.52x10-6 M) [2]
dapolsertib Small molecule or natural product Click here for species-specific activity table Hs Inhibition - - 5
⤷ [5]
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: 6,23
Key to terms and symbols Click column headers to sort
Target used in screen: PIM1
Ligand Sp. Type Action Value Parameter
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.5 pKd
A-674563 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.7 pKd
enzastaurin Small molecule or natural product Hs Inhibitor Inhibition 6.7 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.7 pKd
GSK-461364A Small molecule or natural product Hs Inhibitor Inhibition 6.6 pKd
ruboxistaurin Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.6 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.3 pKd
alvocidib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.3 pKd
GSK690693 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.0 pKd
masitinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 5.9 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: 1,11
Key to terms and symbols Click column headers to sort
Target used in screen: Pim-1/PIM1
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 0.4 -2.0 1.0
isogranulatimide Small molecule or natural product Hs Inhibitor Inhibition 1.4 6.0 2.0
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.5 0.5 0.5
GF109203X Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.3 1.0 1.0
Cdk4 inhibitor Small molecule or natural product Hs Inhibitor Inhibition 8.8 28.0 13.0
Gö 6983 Small molecule or natural product Hs Inhibitor Inhibition 11.6 11.0 1.0
JNK inhibitor V Small molecule or natural product Hs Inhibitor Inhibition 11.6 15.0 3.0
casein kinase II inhibitor III Small molecule or natural product Hs Inhibitor Inhibition 16.2 49.0 6.0
bisindolylmaleimide IV Small molecule or natural product Hs Inhibitor Inhibition 17.2 12.0 0.0
Cdc2-like kinase inhibitor Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 17.9 25.0 4.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immuno Process Associations
Immuno Process:  Immune regulation
Immuno Process:  Immune system development
Immuno Process:  Cytokine production & signalling

References

Show »

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. Battistutta R, Cozza G, Pierre F, Papinutto E, Lolli G, Sarno S, O'Brien SE, Siddiqui-Jain A, Haddach M, Anderes K et al.. (2011) Unprecedented selectivity and structural determinants of a new class of protein kinase CK2 inhibitors in clinical trials for the treatment of cancer. Biochemistry, 50 (39): 8478-88. [PMID:21870818]

3. Burger MT, Han W, Lan J, Nishiguchi G, Bellamacina C, Lindval M, Atallah G, Ding Y, Mathur M, McBride C et al.. (2013) Structure Guided Optimization, in Vitro Activity, and in Vivo Activity of Pan-PIM Kinase Inhibitors. ACS Med Chem Lett, 4 (12): 1193-7. [PMID:24900629]

4. Burger MT, Nishiguchi G, Han W, Lan J, Simmons R, Atallah G, Ding Y, Tamez V, Zhang Y, Mathur M et al.. (2015) Identification of N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (PIM447), a Potent and Selective Proviral Insertion Site of Moloney Murine Leukemia (PIM) 1, 2, and 3 Kinase Inhibitor in Clinical Trials for Hematological Malignancies. J Med Chem, 58 (21): 8373-86. [PMID:26505898]

5. Czardybon W, Brzózka K, Galezowski M, Windak R, Milik M, Zawadzka M, Guzik E, Prokop M, Wilik K, Sabiniarz A et al.. (2014) Novel benzimidazole derivatives as kinase inhibitors. Patent number: WO2014096388A2. Assignee: Selvita S.A.. Priority date: 20/12/2013. Publication date: 26/06/2014.

6. 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]

7. Debdab M, Carreaux F, Renault S, Soundararajan M, Fedorov O, Filippakopoulos P, Lozach O, Babault L, Tahtouh T, Baratte B et al.. (2011) Leucettines, a class of potent inhibitors of cdc2-like kinases and dual specificity, tyrosine phosphorylation regulated kinases derived from the marine sponge leucettamine B: modulation of alternative pre-RNA splicing. J Med Chem, 54 (12): 4172-86. [PMID:21615147]

8. Drygin D, Haddach M, Pierre F, Ryckman DM. (2012) Potential use of selective and nonselective Pim kinase inhibitors for cancer therapy. J Med Chem, 55 (19): 8199-208. [PMID:22924342]

9. Fedorov O, Marsden B, Pogacic V, Rellos P, Müller S, Bullock AN, Schwaller J, Sundström M, Knapp S. (2007) A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci USA, 104 (51): 20523-8. [PMID:18077363]

10. Foulks JM, Carpenter KJ, Luo B, Xu Y, Senina A, Nix R, Chan A, Clifford A, Wilkes M, Vollmer D et al.. (2014) A small-molecule inhibitor of PIM kinases as a potential treatment for urothelial carcinomas. Neoplasia, 16 (5): 403-12. [PMID:24953177]

11. 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]

12. Garcia PD, Langowski JL, Wang Y, Chen M, Castillo J, Fanton C, Ison M, Zavorotinskaya T, Dai Y, Lu J et al.. (2014) Pan-PIM kinase inhibition provides a novel therapy for treating hematologic cancers. Clin Cancer Res, 20 (7): 1834-45. [PMID:24474669]

13. Haddach M, Michaux J, Schwaebe MK, Pierre F, O'Brien SE, Borsan C, Tran J, Raffaele N, Ravula S, Drygin D et al.. (2012) Discovery of CX-6258. A Potent, Selective, and Orally Efficacious pan-Pim Kinases Inhibitor. ACS Med Chem Lett, 3 (2): 135-9. [PMID:24900437]

14. Huber K, Brault L, Fedorov O, Gasser C, Filippakopoulos P, Bullock AN, Fabbro D, Trappe J, Schwaller J, Knapp S et al.. (2012) 7,8-dichloro-1-oxo-β-carbolines as a versatile scaffold for the development of potent and selective kinase inhibitors with unusual binding modes. J Med Chem, 55 (1): 403-13. [PMID:22136433]

15. Koblish H, Li YL, Shin N, Hall L, Wang Q, Wang K, Covington M, Marando C, Bowman K, Boer J et al.. (2018) Preclinical characterization of INCB053914, a novel pan-PIM kinase inhibitor, alone and in combination with anticancer agents, in models of hematologic malignancies. PLoS ONE, 13 (6): e0199108. [PMID:29927999]

16. Koltun ES, Tsuhako AL, Brown DS, Aay N, Arcalas A, Chan V, Du H, Engst S, Ferguson K, Franzini M et al.. (2012) Discovery of XL413, a potent and selective CDC7 inhibitor. Bioorg Med Chem Lett, 22 (11): 3727-31. [PMID:22560567]

17. Li W, Wan X, Zeng F, Xie Y, Wang Y, Zhang W, Li L and Huang N. (2014) More than just a GPCR ligand: structure-based discovery of thioridazine derivatives as Pim-1 kinase inhibitors. Medchemcomm, 5: 507-511.

18. Paiva C, Godbersen JC, Soderquist RS, Rowland T, Kilmarx S, Spurgeon SE, Brown JR, Srinivasa SP, Danilov AV. (2015) Cyclin-Dependent Kinase Inhibitor P1446A Induces Apoptosis in a JNK/p38 MAPK-Dependent Manner in Chronic Lymphocytic Leukemia B-Cells. PLoS ONE, 10 (11): e0143685. [PMID:26606677]

19. Pierre F, Stefan E, Nédellec AS, Chevrel MC, Regan CF, Siddiqui-Jain A, Macalino D, Streiner N, Drygin D, Haddach M et al.. (2011) 7-(4H-1,2,4-Triazol-3-yl)benzo[c][2,6]naphthyridines: a novel class of Pim kinase inhibitors with potent cell antiproliferative activity. Bioorg Med Chem Lett, 21 (22): 6687-92. [PMID:21982499]

20. Qian KC, Wang L, Hickey ER, Studts J, Barringer K, Peng C, Kronkaitis A, Li J, White A, Mische S et al.. (2005) Structural basis of constitutive activity and a unique nucleotide binding mode of human Pim-1 kinase. J Biol Chem, 280 (7): 6130-7. [PMID:15525646]

21. Wang HL, Andrews KL, Booker SK, Canon J, Cee VJ, Chavez Jr F, Chen Y, Eastwood H, Guerrero N, Herberich B et al.. (2019) Discovery of ( R)-8-(6-Methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4- b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-2-((1-methylcyclopropyl)amino)quinazolin-4(3 H)-one, a Potent and Selective Pim-1/2 Kinase Inhibitor for Hematological Malignancies. J Med Chem, 62 (3): 1523-1540. [PMID:30624936]

22. Wang X, Blackaby W, Allen V, Chan GKY, Chang JH, Chiang PC, Diène C, Drummond J, Do S, Fan E et al.. (2019) Optimization of Pan-Pim Kinase Activity and Oral Bioavailability Leading to Diaminopyrazole (GDC-0339) for the Treatment of Multiple Myeloma. J Med Chem, 62 (4): 2140-2153. [PMID:30715878]

23. 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]

24. Xiang Y, Hirth B, Asmussen G, Biemann HP, Bishop KA, Good A, Fitzgerald M, Gladysheva T, Jain A, Jancsics K et al.. (2011) The discovery of novel benzofuran-2-carboxylic acids as potent Pim-1 inhibitors. Bioorg Med Chem Lett, 21 (10): 3050-6. [PMID:21507633]

How to cite this page

PIM family: Pim-1 proto-oncogene, serine/threonine kinase. Last modified on 06/03/2024. Accessed on 06/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2158.