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mitogen-activated protein kinase kinase kinase kinase 1

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Target id: 2085

Nomenclature: mitogen-activated protein kinase kinase kinase kinase 1

Abbreviated Name: HPK1

Family: KHS subfamily

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 833 19q13.2 MAP4K1 mitogen-activated protein kinase kinase kinase kinase 1
Mouse - 827 7 B1 Map4k1 mitogen-activated protein kinase kinase kinase kinase 1
Rat - 827 1 q21 Map4k1 mitogen activated protein kinase kinase kinase kinase 1
Previous and Unofficial Names Click here for help
hematopoietic progenitor kinase 1 | MAPK/ERK kinase kinase kinase 1
Database Links Click here for help
Alphafold Q92918 (Hs), P70218 (Mm)
BRENDA 2.7.11.1
ChEMBL Target CHEMBL5749 (Hs)
Ensembl Gene ENSG00000104814 (Hs), ENSMUSG00000037337 (Mm), ENSRNOG00000020505 (Rn)
Entrez Gene 11184 (Hs), 26411 (Mm), 292763 (Rn)
Human Protein Atlas ENSG00000104814 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:11184 (Hs), mmu:26411 (Mm), rno:292763 (Rn)
OMIM 601983 (Hs)
Pharos Q92918 (Hs)
RefSeq Nucleotide NM_001042600 (Hs), NM_008279 (Mm), NM_001106243 (Rn)
RefSeq Protein NP_001036065 (Hs), NP_032305 (Mm), NP_001099713 (Rn)
UniProtKB Q92918 (Hs), P70218 (Mm)
Wikipedia MAP4K1 (Hs)
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
compound 5i [PMID: 36542759] Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 9.1 pIC50 15
⤷ pIC50 9.1 (IC50 8x10-10 M) [15]
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: 5,17
Key to terms and symbols Click column headers to sort
Target used in screen: HPK1
Ligand Sp. Type Action Value Parameter
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.4 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.8 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 7.8 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.8 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.4 pKd
crizotinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.4 pKd
foretinib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.4 pKd
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 7.4 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 7.2 pKd
tozasertib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.1 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
HPK1 (MAP4K1) is highly expressed in hematopoietic cell subsets. It acts as a critical negative regulator in the activation of T cells and dendritic cells [6,13].
HPK1 inhibits T cell receptor (TCR) signaling via a mechanism that induces phosphorylation and ubiquitination of SLP-76 and it inhibits B cell receptor signaling by inducing phosphorylation and ubiquitination of BLNK [16].
Small molecule HPK1 inhibitors are predicted to induce immune responses in the tumour microenvironment [9], and are subsequently being investigated for immuno-oncology potential [10-11]. For example, Nimbus Therapeutics (in partnership with Celgene) have a declared HPK1 program in their development pipeline. Other pharmaceutical companies hold patents which claim HPK1 inhibitors [2-3,18].
Cell Type Associations
Immuno Cell Type:  T cells
References:  4,7-8
Immuno Cell Type:  B cells
Cell Ontology Term:   B cell (CL:0000236)
References:  4
Immuno Cell Type:  Mast cells
Cell Ontology Term:   mast cell (CL:0000097)
References:  4
Immuno Cell Type:  Macrophages & monocytes
Cell Ontology Term:   macrophage (CL:0000235)
References:  4
Immuno Cell Type:  Granulocytes
Cell Ontology Term:   neutrophil (CL:0000775)
References:  4
Immuno Cell Type:  Dendritic cells
Cell Ontology Term:   dendritic cell (CL:0000451)
References:  4
Physiological Consequences of Altering Gene Expression Click here for help
Mice with hpk1 knock-out show enhanced T cell activation, increased cytokine production, and increased antibody production after KLH immunization. These findings confirm that hpk1 is a negative regulator of T cell receptor signalling and T cell-mediated immune responses.
Species:  Mouse
Tissue: 
Technique: 
References:  12
Hpk1 null mice are more susceptible to experimental autoimmune encephalomyelitis indiction.
Species:  Mouse
Tissue: 
Technique: 
References:  12
Dendritic cells from hpk1-deficient mice produce higher levels of co-stimulatory molecules and proinflammatory cytokines than their wild type counterpatrs.
Species:  Mouse
Tissue: 
Technique: 
References:  1
General Comments
Hematopoietic progenitor kinase 1 (HPK1) regulates stress responses, proliferation, and apoptosis in hematopoietic cells. HPK1 has been identified as a novel target for cancer immunotherapy, whose inhibition may activate anti-tumour activity of both dendritic cells and T cells [11]. In contrast, a specific role of HPK1 as a novel tumor suppressor has been suggested by studies in pancreatic cancer [14].

References

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1. Alzabin S, Bhardwaj N, Kiefer F, Sawasdikosol S, Burakoff S. (2009) Hematopoietic progenitor kinase 1 is a negative regulator of dendritic cell activation. J Immunol, 182 (10): 6187-94. [PMID:19414772]

2. Araujo EMV, Chen Y, Dasgupta B, Degnan AP, Hill MD, Kumi GK, Mastalerz HA, Wittman MD, Pearce BC, Zhang G. (2019) Isofuranone compounds useful as hpk1 inhibitors. Patent number: WO2019090198A1. Assignee: Bristol-Myers Squibb. Priority date: 06/11/2017. Publication date: 09/05/2019.

3. Chan B, Drobnick J, Gazzard L, Heffron T, Liang J, Malhotra S, Mendonca R, Rajapaksa N, Stivala C, Tellis J, et al.. (2018) Isoquinolines as inhibitors of hpk1. Patent number: WO2018183964A1. Assignee: Genentech, Hoffmann-La Roche. Priority date: 30/03/2017. Publication date: 04/10/2018.

4. Chuang HC, Wang X, Tan TH. (2016) MAP4K Family Kinases in Immunity and Inflammation. Adv Immunol, 129: 277-314. [PMID:26791862]

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. Hernandez S, Qing J, Thibodeau RH, Du X, Park S, Lee HM, Xu M, Oh S, Navarro A, Roose-Girma M et al.. (2018) The Kinase Activity of Hematopoietic Progenitor Kinase 1 Is Essential for the Regulation of T Cell Function. Cell Rep, 25 (1): 80-94. [PMID:30282040]

7. Hu MC, Qiu WR, Wang X, Meyer CF, Tan TH. (1996) Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade. Genes Dev, 10 (18): 2251-64. [PMID:8824585]

8. Kiefer F, Tibbles LA, Anafi M, Janssen A, Zanke BW, Lassam N, Pawson T, Woodgett JR, Iscove NN. (1996) HPK1, a hematopoietic protein kinase activating the SAPK/JNK pathway. EMBO J, 15 (24): 7013-25. [PMID:9003777]

9. Liu J, Curtin J, You D, Hillerman S, Li-Wang B, Eraslan R, Xie J, Swanson J, Ho CP, Oppenheimer S et al.. (2019) Critical role of kinase activity of hematopoietic progenitor kinase 1 in anti-tumor immune surveillance. PLoS ONE, 14 (3): e0212670. [PMID:30913212]

10. Sawasdikosol S, Burakoff S. (2019) The Structure of HPK1 Kinase Domain: To Boldly Go Where No Immuno-Oncology Drugs Have Gone Before. Structure, 27 (1): 1-3. [PMID:30605659]

11. Sawasdikosol S, Zha R, Yang B, Burakoff S. (2012) HPK1 as a novel target for cancer immunotherapy. Immunol Res, 54 (1-3): 262-5. [PMID:22477524]

12. Shui JW, Boomer JS, Han J, Xu J, Dement GA, Zhou G, Tan TH. (2007) Hematopoietic progenitor kinase 1 negatively regulates T cell receptor signaling and T cell-mediated immune responses. Nat Immunol, 8 (1): 84-91. [PMID:17115060]

13. Simon SI. (2013) Gimme a brake: HPK1 regulates LFA-1 and neutrophil traction. Blood, 121 (20): 4017-8. [PMID:23682030]

14. Wang H, Song X, Logsdon C, Zhou G, Evans DB, Abbruzzese JL, Hamilton SR, Tan TH, Wang H. (2009) Proteasome-mediated degradation and functions of hematopoietic progenitor kinase 1 in pancreatic cancer. Cancer Res, 69 (3): 1063-70. [PMID:19141650]

15. Wang MS, Wang ZZ, Li ZL, Gong Y, Duan CX, Cheng QH, Huang W, Yang GF. (2023) Discovery of Macrocycle-Based HPK1 Inhibitors for T-Cell-Based Immunotherapy. J Med Chem, 66 (1): 611-626. [PMID:36542759]

16. Wang X, Li JP, Kuo HK, Chiu LL, Dement GA, Lan JL, Chen DY, Yang CY, Hu H, Tan TH. (2012) Down-regulation of B cell receptor signaling by hematopoietic progenitor kinase 1 (HPK1)-mediated phosphorylation and ubiquitination of activated B cell linker protein (BLNK). J Biol Chem, 287 (14): 11037-48. [PMID:22334673]

17. 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]

18. Ye H-F, Vechorkin O, Pan J, Liu K, Sokolsky A, Wamg A, Ye Q, Yao W. (2018) Pyrazolopyridine derivatives as hpk1 modulators and uses thereof for the treatment of cancer . Patent number: WO2018049200A1. Assignee: Incyte Corporation. Priority date: 09/09/2016. Publication date: 15/03/2018.

How to cite this page

KHS subfamily: mitogen-activated protein kinase kinase kinase kinase 1. Last modified on 25/01/2023. Accessed on 16/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2085.