Target Information

Target General Information

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Target ID

T55709 (Former ID: TTDR00805)

Target Name

Choline kinase (CHKA)

Synonyms

ChoK; CHKA; CHETK-alpha

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Gene Name

CHKA

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Function

Has a key role in phospholipid biosynthesis and may contribute to tumor cell growth. Catalyzes the first step in phosphatidylcholine biosynthesis. Contributes to phosphatidylethanolamine biosynthesis. Phosphorylates choline and ethanolamine. Has higher activity with choline.

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BioChemical Class

Kinase

UniProt ID

CHKA_HUMAN

EC Number

EC 2.7.1.32

Sequence

MKTKFCTGGEAEPSPLGLLLSCGSGSAAPAPGVGQQRDAASDLESKQLGGQQPPLALPPP
PPLPLPLPLPQPPPPQPPADEQPEPRTRRRAYLWCKEFLPGAWRGLREDEFHISVIRGGL
SNMLFQCSLPDTTATLGDEPRKVLLRLYGAILQMRSCNKEGSEQAQKENEFQGAEAMVLE
SVMFAILAERSLGPKLYGIFPQGRLEQFIPSRRLDTEELSLPDISAEIAEKMATFHGMKM
PFNKEPKWLFGTMEKYLKEVLRIKFTEESRIKKLHKLLSYNLPLELENLRSLLESTPSPV
VFCHNDCQEGNILLLEGRENSEKQKLMLIDFEYSSYNYRGFDIGNHFCEWMYDYSYEKYP
FFRANIRKYPTKKQQLHFISSYLPAFQNDFENLSTEEKSIIKEEMLLEVNRFALASHFLW
GLWSIVQAKISSIEFGYMDYAQARFDAYFHQKRKLGV

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3D Structure

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PDB

HIT2.0 ID

T10CBH

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

TCD-717

Drug Info

Phase 1

Solid tumour/cancer

[2]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 1 Inhibitor drugs

TCD-717

Drug Info

[1]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: TCD-717

Ligand Info

Structure Description

Choline Kinase Alpha in Complex with TCD-717

PDB:5W6O

Method

X-ray diffraction

Resolution

2.35 Å

Mutation

[3]

PDB Sequence

EQPEPRTRRR

⁹⁰

AYLWCKEFLP

¹⁰⁰

GAWRGLREDE

¹¹⁰

FHISVIRGGL

¹²⁰

SNMLFQCSLP

¹³⁰

DTTATLGDEP

¹⁴⁰

RKVLLRLYGE

¹⁷⁵

AMVLESVMFA

¹⁸⁵

ILAERSLGPK

¹⁹⁵

LYGIFPQGRL

²⁰⁵

EQFIPSRRLD

²¹⁵

TEELSLPDIS

²²⁵

AEIAEKMATF

²³⁵

HGMKMPFNKE

²⁴⁵

PKWLFGTMEK

²⁵⁵

YLKEVLRIKF

²⁶⁵

TEESRIKKLH

²⁷⁵

KLLSYNLPLE

²⁸⁵

LENLRSLLES

²⁹⁵

TPSPVVFCHN

³⁰⁵

DCQEGNILLL

³¹⁵

EGRENSEKQK

³²⁵

LMLIDFEYSS

³³⁵

YNYRGFDIGN

³⁴⁵

HFCEWMYDYS

³⁵⁵

YEKYPFFRAN

³⁶⁵

IRKYPTKKQQ

³⁷⁵

LHFISSYLPA

³⁸⁵

FQNDFENLST

³⁹⁵

EEKSIIKEEM

⁴⁰⁵

LLEVNRFALA

⁴¹⁵

SHFLWGLWSI

⁴²⁵

VQAKISSIEF

⁴³⁵

GYMDYAQARF

⁴⁴⁵

DAYFHQKRKL

⁴⁵⁵

Residue

Distance (Å)

TYR148

3.206

GLY149

3.753

ALA176

3.785

MET177

3.294

GLU180

3.690

SER181

4.009

ILE199

3.825

PHE200

3.085

PRO201

3.542

GLY203

4.958

TRP248

4.139

LEU249

3.805

Residue

Distance (Å)

THR252

3.563

TYR256

3.156

ASN305

3.949

GLU332

3.732

TYR333

3.096

SER334

4.292

SER335

4.570

ASN337

3.268

PHE341

3.678

LEU419

3.730

TRP420

3.722

TRP423

3.993

Ligand Name: adenosine diphosphate

Ligand Info

Structure Description

Crystal structure of human choline kinase alpha in complex with hemicholinium-3 and ADP

PDB:3G15

Method

X-ray diffraction

Resolution

1.70 Å

Mutation

Yes

[4]

PDB Sequence

EQPEPRTRRR

⁹⁰

AYLWCKEFLP

¹⁰⁰

GAWRGLREDE

¹¹⁰

FHISVIRGGL

¹²⁰

SNMLFQCSLP

¹³⁰

DTTATLGDEP

¹⁴⁰

RKVLLRLYGA

¹⁵⁰

AEAMVLESVM

¹⁸³

FAILAERSLG

¹⁹³

PKLYGIFPQG

²⁰³

RLEQFIPSRR

²¹³

LDTEELSLPD

²²³

ISAEIAEKMA

²³³

TFHGMKMPFN

²⁴³

KEPKWLFGTM

²⁵³

EKYLKEVLRI

²⁶³

KFTEESRIKK

²⁷³

LHKLLSYNLP

²⁸³

LELENLRSLL

²⁹³

ESTPSPVVFC

³⁰³

HNDCQEGNIL

³¹³

LLEGRENSEK

³²³

QKLMLIDFEY

³³³

SSYNYRGFDI

³⁴³

GNHFCEWMYD

³⁵³

YSYEKYPFFR

³⁶³

ANIRKYPTKK

³⁷³

QQLHFISSYL

³⁸³

PAFQNDFENL

³⁹³

STEEKSIIKE

⁴⁰³

EMLLEVNRFA

⁴¹³

LASHFLWGLW

⁴²³

SIVQAKISSI

⁴³³

EFGYMDYAQA

⁴⁴³

RFDAYFHQKR

⁴⁵³

KLGV

Residue

Distance (Å)

ILE116

4.856

ARG117

2.476

ASN122

4.414

LEU124

3.491

LEU144

3.549

ARG146

2.873

PRO194

3.604

GLU206

4.386

GLN207

2.814

PHE208

3.799

Residue

Distance (Å)

ILE209

2.924

SER211

4.179

ARG213

3.045

GLY310

2.507

ASN311

2.927

LEU313

3.912

ILE329

3.418

ASP330

2.942

GLU332

2.757

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Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
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

Different Human System Profiles of Target

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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

There is no similarity protein (E value < 0.005) for this target


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.

KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
Glycerophospholipid metabolism	hsa00564	Affiliated Target
Class: Metabolism => Lipid metabolism	Pathway Hierarchy

Degree	4	Degree centrality	4.30E-04	Betweenness centrality	2.03E-04
Closeness centrality	1.32E-01	Radiality	1.12E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	4.00E+00	Topological coefficient	4.29E-01	Eccentricity	15
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Affiliated Biological Pathways

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BioCyc

[+] 1 BioCyc Pathways

Phosphatidylcholine biosynthesis

KEGG Pathway

[+] 3 KEGG Pathways

Glycerophospholipid metabolism

Metabolic pathways

Choline metabolism in cancer

Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Phospholipid Biosynthesis

WikiPathways

[+] 2 WikiPathways

Acetylcholine Synthesis

Glycerophospholipid biosynthesis

Target-Related Models and Studies

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Target Validation

Target Validation Info

Target QSAR Model

References

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REF 1

National Cancer Institute Drug Dictionary (drug id 687183).

REF 2

ClinicalTrials.gov (NCT01215864) Study of Intravenous TCD-717 in Patients With Advanced Solid Tumors. U.S. National Institutes of Health.

REF 3

Identification of a Unique Inhibitor-Binding Site on Choline Kinase Alpha. Biochemistry. 2018 Feb 27;57(8):1316-1325.

REF 4

Crystal structures of human choline kinase isoforms in complex with hemicholinium-3: single amino acid near the active site influences inhibitor sensitivity. J Biol Chem. 2010 May 21;285(21):16330-40.

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