Target Information
| Target General Information | Top | |||||
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| Target ID |
T00749
(Former ID: TTDNR00707)
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| Target Name |
MEK kinase kinase 1 (MAP4K1)
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| Synonyms |
Mitogen-activated protein kinase kinase kinase kinase 1; MEKKK 1; MAPK/ERK kinase kinase kinase 1; Hematopoietic progenitor kinase; HPK1
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| Gene Name |
MAP4K1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| Function |
Appears to act upstream of the JUN N-terminal pathway. May play a role in hematopoietic lineage decisions and growth regulation. Able to autophosphorylate. Serine/threonine-protein kinase, which may play a role in the response to environmental stress.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.11.1
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| Sequence |
MDVVDPDIFNRDPRDHYDLLQRLGGGTYGEVFKARDKVSGDLVALKMVKMEPDDDVSTLQ
KEILILKTCRHANIVAYHGSYLWLQKLWICMEFCGAGSLQDIYQVTGSLSELQISYVCRE VLQGLAYLHSQKKIHRDIKGANILINDAGEVRLADFGISAQIGATLARRLSFIGTPYWMA PEVAAVALKGGYNELCDIWSLGITAIELAELQPPLFDVHPLRVLFLMTKSGYQPPRLKEK GKWSAAFHNFIKVTLTKSPKKRPSATKMLSHQLVSQPGLNRGLILDLLDKLKNPGKGPSI GDIEDEEPELPPAIPRRIRSTHRSSSLGIPDADCCRRHMEFRKLRGMETRPPANTARLQP PRDLRSSSPRKQLSESSDDDYDDVDIPTPAEDTPPPLPPKPKFRSPSDEGPGSMGDDGQL SPGVLVRCASGPPPNSPRPGPPPSTSSPHLTAHSEPSLWNPPSRELDKPPLLPPKKEKMK RKGCALLVKLFNGCPLRIHSTAAWTHPSTKDQHLLLGAEEGIFILNRNDQEATLEMLFPS RTTWVYSINNVLMSLSGKTPHLYSHSILGLLERKETRAGNPIAHISPHRLLARKNMVSTK IQDTKGCRACCVAEGASSGGPFLCGALETSVVLLQWYQPMNKFLLVRQVLFPLPTPLSVF ALLTGPGSELPAVCIGVSPGRPGKSVLFHTVRFGALSCWLGEMSTEHRGPVQVTQVEEDM VMVLMDGSVKLVTPEGSPVRGLRTPEIPMTEAVEAVAMVGGQLQAFWKHGVQVWALGSDQ LLQELRDPTLTFRLLGSPRLECSGTISPHCNLLLPGSSNSPASASRVAGITGL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | CFI-402411 | Drug Info | Phase 1/2 | Solid tumour/cancer | [2] | |
| 2 | BGB-15025 | Drug Info | Phase 1 | Solid tumour/cancer | [3] | |
| 3 | PF-07265028 | Drug Info | Phase 1 | Aggressive cancer | [4] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 3 Inhibitor drugs | + | ||||
| 1 | CFI-402411 | Drug Info | [5] | |||
| 2 | BGB-15025 | Drug Info | [3] | |||
| 3 | PF-07265028 | Drug Info | [6] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Sunitinib | Ligand Info | |||||
| Structure Description | Crystal structure of HPK1 kinase domain T165E,S171E phosphomimetic mutant in complex with sunitinib in the inactive state. | PDB:6NG0 | ||||
| Method | X-ray diffraction | Resolution | 2.05 Å | Mutation | Yes | [7] |
| PDB Sequence |
PDIFNRDPRD
15 HYDLLQRLGG25 GEVFKARDKV38 SGDLVALKMV48 KMEPDDDVST58 LQKEILILKT 68 CRHANIVAYH78 GSYLWLQKLW88 ICMEFCGAGS98 LQDIYQVTGS108 LSELQISYVC 118 REVLQGLAYL128 HSQKKIHRDI138 KGANILINDA148 GEVRLADFGI158 SALARRLEFI 173 GTPYWMAPEV183 AAVALKGGYN193 ELCDIWSLGI203 TAIELAELQP213 PLFDVHPLRV 223 LFLMTKSGYQ233 PPRLKEKGKW243 SAAFHNFIKV253 TLTKSPKKRP263 SATKMLSHQL 273 VSQPGLNRGL283 ILDLLDKLKN293 PGKGPSIGD
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: L-serine-O-phosphate | Ligand Info | |||||
| Structure Description | Crystal structure of diphosphorylated HPK1 kinase domain in complex with sunitinib in the active state. | PDB:6NFZ | ||||
| Method | X-ray diffraction | Resolution | 2.97 Å | Mutation | No | [7] |
| PDB Sequence |
DIFNRDPRDH
16 YDLLQRLGTY28 GEVFKARDKV38 SGDLVALKMV48 TLQKEILILK67 TCRHANIVAY 77 HGSYLWICME92 FCGAGSLQDI102 YQVTGSLSEL112 QISYVCREVL122 QGLAYLHSQK 132 KIHRDIKGAN142 ILINDAGEVR152 LADFGISAQI162 GALARRLFIG174 TPYWMAPEVA 184 AVALKGGYNE194 LCDIWSLGIT204 AIELAELQPP214 LFDVHPLRVL224 FLMTKSGYQP 234 PRLKEKGKWS244 AAFHNFIKVT254 LTKSPKKRPS264 ATKMLSHQLV274 SQPGLNRGLI 284 LDLLDKLK
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| MAPK signaling pathway | hsa04010 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Degree | 6 | Degree centrality | 6.45E-04 | Betweenness centrality | 6.05E-05 |
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| Closeness centrality | 2.02E-01 | Radiality | 1.35E+01 | Clustering coefficient | 1.33E-01 |
| Neighborhood connectivity | 2.08E+01 | Topological coefficient | 2.36E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| References | Top | |||||
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| REF 1 | MAP4K Family Kinases in Immunity and Inflammation. Adv Immunol. 2016;129:277-314. | |||||
| REF 2 | ClinicalTrials.gov (NCT04521413) Safety and Efficacy Study Of CFI-402411 in Subjects With Advanced Solid Malignancies. U.S. National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT04649385) BGB-15025 Alone and in Combination With Anti-PD-1 Monoclonal Antibody Tislelizumab in Participants With Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT05233436) A PHASE 1, OPEN-LABEL, DOSE ESCALATION AND EXPANSION STUDY OF PF-07265028 AS A SINGLE AGENT AND IN COMBINATION WITH SASANLIMAB EVALUATING THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS, AND ANTI-TUMOR ACTIVITY OF PF-07265028 IN PARTICIPANTS WITH ADVANCED OR METASTATIC SOLID TUMORS. U.S.National Institutes of Health. | |||||
| REF 5 | Clinical pipeline report, company report or official report of Treadwell Therapeutics. | |||||
| REF 6 | Clinical pipeline report, company report or official report of Pfizer | |||||
| REF 7 | Multiple conformational states of the HPK1 kinase domain in complex with sunitinib reveal the structural changes accompanying HPK1 trans-regulation. J Biol Chem. 2019 Jun 7;294(23):9029-9036. | |||||
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