Target Information

Target General Information

Target ID

T81358 (Former ID: TTDI02039)

Target Name

CDC7-related kinase (CDC7)

Synonyms

huCdc7; HsCdc7; Cell division cycle 7related protein kinase; Cell division cycle 7-related protein kinase; CDC7related kinase; CDC7L1

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Gene Name

CDC7

Target Type

Clinical trial target

[1]

Disease

[+] 2 Target-related Diseases

Malignant haematopoietic neoplasm [ICD-11: 2B33]

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

Function

Can phosphorylates MCM2 and MCM3. Seems to phosphorylate critical substrates that regulate the G1/S phase transition and/or DNA replication.

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BioChemical Class

Kinase

UniProt ID

CDC7_HUMAN

EC Number

EC 2.7.11.1

Sequence

MEASLGIQMDEPMAFSPQRDRFQAEGSLKKNEQNFKLAGVKKDIEKLYEAVPQLSNVFKI
EDKIGEGTFSSVYLATAQLQVGPEEKIALKHLIPTSHPIRIAAELQCLTVAGGQDNVMGV
KYCFRKNDHVVIAMPYLEHESFLDILNSLSFQEVREYMLNLFKALKRIHQFGIVHRDVKP
SNFLYNRRLKKYALVDFGLAQGTHDTKIELLKFVQSEAQQERCSQNKSHIITGNKIPLSG
PVPKELDQQSTTKASVKRPYTNAQIQIKQGKDGKEGSVGLSVQRSVFGERNFNIHSSISH
ESPAVKLMKQSKTVDVLSRKLATKKKAISTKVMNSAVMRKTASSCPASLTCDCYATDKVC
SICLSRRQQVAPRAGTPGFRAPEVLTKCPNQTTAIDMWSAGVIFLSLLSGRYPFYKASDD
LTALAQIMTIRGSRETIQAAKTFGKSILCSKEVPAQDLRKLCERLRGMDSSTPKLTSDIQ
GHASHQPAISEKTDHKASCLVQTPPGQYSGNSFKKGDSNSCEHCFDEYNTNLEGWNEVPD
EAYDLLDKLLDLNPASRITAEEALLHPFFKDMSL

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3D Structure

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PDB

HIT2.0 ID

T51RUY

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

BMS-863233

Drug Info

Phase 1/2

Haematological malignancy

[2], [3]

TAK-931

Drug Info

Phase 1

Solid tumour/cancer

[4]

Mode of Action

[+] 2 Modes of Action

Modulator

[+] 2 Modulator drugs

BMS-863233

Drug Info

[1], [5]

PHA-767491

Drug Info

[7]

Inhibitor

[+] 6 Inhibitor drugs

TAK-931

Drug Info

[4]

PMID26161698-Compound-44

Drug Info

[6]

PMID19115845C89S

Drug Info

[8]

PMID20873740C18

Drug Info

[9]

PMID24793884C74

Drug Info

[10]

PMID24793884C77

Drug Info

[10]

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: Boric acid

Ligand Info

Structure Description

Minimal construct of Cdc7-Dbf4 bound to XL413

PDB:6YA6

Method

X-ray diffraction

Resolution

1.44 Å

Mutation

[11]

PDB Sequence

AGVKKDIEKL

⁴⁷

YEAVPQLSNV

⁵⁷

FKIEDKIGEG

⁶⁷

TFSSVYLATA

⁷⁷

QLQVGPEEKI

⁸⁷

ALKHLIPTSH

⁹⁷

PIRIAAELQC

¹⁰⁷

LTVAGGQDNV

¹¹⁷

MGVKYCFRKN

¹²⁷

DHVVIAMPYL

¹³⁷

EHESFLDILN

¹⁴⁷

SLSFQEVREY

¹⁵⁷

MLNLFKALKR

¹⁶⁷

IHQFGIVHRD

¹⁷⁷

VKPSNFLYNR

¹⁸⁷

RLKKYALVDF

¹⁹⁷

GLAQGTHDTK

²⁰⁷

IELLKFVQPA

³⁴⁷

SLTCDCYATD

³⁵⁷

KVCSICLSRR

³⁶⁷

QQVAPRAGTP

³⁷⁷

GFRAPEVLTK

³⁸⁷

CPNQTTAIDM

³⁹⁷

WSAGVIFLSL

⁴⁰⁷

LSGRYPFYKA

⁴¹⁷

SDDLTALAQI

⁴²⁷

MTIRGSRETI

⁴³⁷

QAAKTFGKSI

⁴⁴⁷

LCSKEVPAQD

⁴⁵⁷

LRKLCERLRG

⁴⁶⁷

AGAGGWNEVP

⁵³⁹

DEAYDLLDKL

⁵⁴⁹

LDLNPASRIT

⁵⁵⁹

AEEALLHPFF

⁵⁶⁹

KDMS

Residue

Distance (Å)

LEU79

4.818

PRO83

4.510

GLU84

3.808

Residue

Distance (Å)

GLU85

2.816

LYS86

4.752

Ligand Name: BMS-863233

Ligand Info

Structure Description

Minimal construct of Cdc7-Dbf4 bound to XL413

PDB:6YA6

Method

X-ray diffraction

Resolution

1.44 Å

Mutation

[11]

PDB Sequence

AGVKKDIEKL

⁴⁷

YEAVPQLSNV

⁵⁷

FKIEDKIGEG

⁶⁷

TFSSVYLATA

⁷⁷

QLQVGPEEKI

⁸⁷

ALKHLIPTSH

⁹⁷

PIRIAAELQC

¹⁰⁷

LTVAGGQDNV

¹¹⁷

MGVKYCFRKN

¹²⁷

DHVVIAMPYL

¹³⁷

EHESFLDILN

¹⁴⁷

SLSFQEVREY

¹⁵⁷

MLNLFKALKR

¹⁶⁷

IHQFGIVHRD

¹⁷⁷

VKPSNFLYNR

¹⁸⁷

RLKKYALVDF

¹⁹⁷

GLAQGTHDTK

²⁰⁷

IELLKFVQPA

³⁴⁷

SLTCDCYATD

³⁵⁷

KVCSICLSRR

³⁶⁷

QQVAPRAGTP

³⁷⁷

GFRAPEVLTK

³⁸⁷

CPNQTTAIDM

³⁹⁷

WSAGVIFLSL

⁴⁰⁷

LSGRYPFYKA

⁴¹⁷

SDDLTALAQI

⁴²⁷

MTIRGSRETI

⁴³⁷

QAAKTFGKSI

⁴⁴⁷

LCSKEVPAQD

⁴⁵⁷

LRKLCERLRG

⁴⁶⁷

AGAGGWNEVP

⁵³⁹

DEAYDLLDKL

⁵⁴⁹

LDLNPASRIT

⁵⁵⁹

AEEALLHPFF

⁵⁶⁹

KDMS

Residue

Distance (Å)

ILE64

4.004

GLY65

3.841

GLU66

3.781

GLY67

3.716

SER70

3.268

VAL72

3.661

ALA88

3.294

LYS90

2.769

GLU104

4.369

MET118

3.781

MET134

3.241

Residue

Distance (Å)

PRO135

3.455

TYR136

3.408

LEU137

3.526

HIS139

3.793

SER181

4.449

ASN182

2.814

LEU184

3.470

VAL195

3.482

ASP196

2.886

PHE197

4.945

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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

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Titin (TTN)		22.222 (24/108)	2.00E-04
Hematopoietic cell kinase (HCK)	PF07714 ; PF00017 ; PF00018 More >>	24.277 (42/173)	2.94E-04
Proto-oncogene c-Src (SRC)	PF07714 ; PF00017 ; PF00018 More >>	23.718 (37/156)	3.55E-04
Angiopoietin 1 receptor (TEK)	PF00041 ; PF10430 ; PF07714 More >>	23.077 (39/169)	4.89E-04
Yes tyrosine kinase (YES)	PF07714 ; PF00017 ; PF00018 More >>	22.326 (48/215)	5.40E-04
Ephrin type-A receptor 1 (EPHA1)	PF14575 ; PF01404 ; PF07699 ; PF00041 ; PF07714 ; PF00536 More >>	20.930 (63/301)	7.77E-04
Tie-1 tyrosine kinase receptor (TIE1)	PF00041 ; PF00047 ; PF07714 More >>	22.424 (37/165)	1.00E-03
Mixed lineage kinase 2 (MAP3K10)	PF07714 ; PF14604	24.242 (40/165)	2.00E-03
Ephrin type-A receptor 7 (EPHA7)	PF14575 ; PF01404 ; PF07699 ; PF00041 ; PF07714 ; PF00536 More >>	23.013 (55/239)	2.00E-03
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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.

KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
Cell cycle	hsa04110	Affiliated Target
Class: Cellular Processes => Cell growth and death	Pathway Hierarchy

Degree	24	Degree centrality	2.58E-03	Betweenness centrality	2.15E-04
Closeness centrality	2.10E-01	Radiality	1.37E+01	Clustering coefficient	6.38E-01
Neighborhood connectivity	4.05E+01	Topological coefficient	2.02E-01	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target-interacting Proteins

Target-interacting Proteins Info

Target Affiliated Biological Pathways

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NetPath Pathway

[+] 1 NetPath Pathways

TGF_beta_Receptor Signaling Pathway

References

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REF 1

Discovery of XL413, a potent and selective CDC7 inhibitor. Bioorg Med Chem Lett. 2012 Jun 1;22(11):3727-31.

REF 2

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8113).

REF 3

ClinicalTrials.gov (NCT00838890) A Study of BMS-863233 in Patients With Hematologic Cancer. U.S. National Institutes of Health.

REF 4

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 5

The potent Cdc7-Dbf4 (DDK) kinase inhibitor XL413 has limited activity in many cancer cell lines and discovery of potential new DDK inhibitor scaffolds.PLoS One.2014 Nov 20;9(11):e113300.

REF 6

Cyclin-dependent kinase inhibitors for cancer therapy: a patent review (2009 - 2014).Expert Opin Ther Pat. 2015;25(9):953-70.

REF 7

Drug design with Cdc7 kinase: a potential novel cancer therapy target. Drug Des Devel Ther. 2009 Feb 6;2:255-64.

REF 8

First Cdc7 kinase inhibitors: pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery. J Med Chem. 2009 Jan 22;52(2):293-307.

REF 9

Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding. J Med Chem. 2010 Oct 28;53(20):7296-315.

REF 10

Synthesis and structure-activity relationship of trisubstituted thiazoles as Cdc7 kinase inhibitors. Eur J Med Chem. 2014 Jun 10;80:364-82.

REF 11

Structural Basis for the Activation and Target Site Specificity of CDC7 Kinase. Structure. 2020 Aug 4;28(8):954-962.e4.

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