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Target id: 2085
Nomenclature: mitogen-activated protein kinase kinase kinase kinase 1
Abbreviated Name: HPK1
Family: KHS subfamily
Gene and Protein Information | ||||||
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 |
hematopoietic progenitor kinase 1 | MAPK/ERK kinase kinase kinase 1 |
Database Links | |
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 | ||||
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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 | |||||||||||||||||||||||||||||||||||||||||||||||||
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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: 5,17 |
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Target used in screen: HPK1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 | ||||||
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Physiological Consequences of Altering Gene Expression | ||||||||||
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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]. |
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.
KHS subfamily: mitogen-activated protein kinase kinase kinase kinase 1. Last modified on 25/01/2023. Accessed on 03/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2085.