Target Information

Target General Information

Target ID

T07173 (Former ID: TTDC00318)

Target Name

Tropomyosin-related kinase A (TrkA)

Synonyms

gp140trk; Tyrosine kinase receptor A; Tyrosine kinase receptor; Trk-A; TRKA; TRK1-transforming tyrosine kinase protein; TRK1 transforming tyrosinekinase protein; TRK; P140-TrkA; Neurotrophic tyrosine kinase receptor type 1; NGF-trk receptor type A; MTC; High affinity nerve growth factor receptor

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Gene Name

NTRK1

Target Type

Successful target

[1]

Disease

[+] 2 Target-related Diseases

Non-small-cell lung cancer [ICD-11: 2C25]

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

Function

High affinity receptor for NGF which is its primary ligand. Can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival. Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors. Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons.

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BioChemical Class

Kinase

UniProt ID

NTRK1_HUMAN

EC Number

EC 2.7.10.1

Sequence

MLRGGRRGQLGWHSWAAGPGSLLAWLILASAGAAPCPDACCPHGSSGLRCTRDGALDSLH
HLPGAENLTELYIENQQHLQHLELRDLRGLGELRNLTIVKSGLRFVAPDAFHFTPRLSRL
NLSFNALESLSWKTVQGLSLQELVLSGNPLHCSCALRWLQRWEEEGLGGVPEQKLQCHGQ
GPLAHMPNASCGVPTLKVQVPNASVDVGDDVLLRCQVEGRGLEQAGWILTELEQSATVMK
SGGLPSLGLTLANVTSDLNRKNVTCWAENDVGRAEVSVQVNVSFPASVQLHTAVEMHHWC
IPFSVDGQPAPSLRWLFNGSVLNETSFIFTEFLEPAANETVRHGCLRLNQPTHVNNGNYT
LLAANPFGQASASIMAAFMDNPFEFNPEDPIPVSFSPVDTNSTSGDPVEKKDETPFGVSV
AVGLAVFACLFLSTLLLVLNKCGRRNKFGINRPAVLAPEDGLAMSLHFMTLGGSSLSPTE
GKGSGLQGHIIENPQYFSDACVHHIKRRDIVLKWELGEGAFGKVFLAECHNLLPEQDKML
VAVKALKEASESARQDFQREAELLTMLQHQHIVRFFGVCTEGRPLLMVFEYMRHGDLNRF
LRSHGPDAKLLAGGEDVAPGPLGLGQLLAVASQVAAGMVYLAGLHFVHRDLATRNCLVGQ
GLVVKIGDFGMSRDIYSTDYYRVGGRTMLPIRWMPPESILYRKFTTESDVWSFGVVLWEI
FTYGKQPWYQLSNTEAIDCITQGRELERPRACPPEVYAIMRGCWQREPQQRHSIKDVHAR
LQALAQAPPVYLDVLG

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3D Structure

Click to Show 3D Structure of This Target

AlphaFold

HIT2.0 ID

T75OVL

Drugs and Modes of Action

Top

Approved Drug(s)

[+] 3 Approved Drugs

Entrectinib

Drug Info

Approved

Non-small-cell lung cancer

[2]

Larotrectinib

Drug Info

Approved

Solid tumour/cancer

[3]

Repotrectinib

Drug Info

Approved

Non-small-cell lung cancer

[4]

Clinical Trial Drug(s)

[+] 8 Clinical Trial Drugs

MIM-D3

Drug Info

Phase 3

Alzheimer disease

[5]

CT 327

Drug Info

Phase 2

Psoriasis vulgaris

[6]

SNA-120

Drug Info

Phase 2

Plaque psoriasis

[7]

ONO-7579

Drug Info

Phase 1/2

Solid tumour/cancer

[3]

Altiratinib

Drug Info

Phase 1

Solid tumour/cancer

[9]

DS-6051

Drug Info

Phase 1

Solid tumour/cancer

[10]

LOXO-195

Drug Info

Phase 1

Solid tumour/cancer

[3]

PLX7486

Drug Info

Phase 1

Pancreatic cancer

[11]

Patented Agent(s)

[+] 61 Patented Agents

3-amino-5-benzyl-substituted indazole derivative 1

Drug Info

Patented

Pruritus

[12]

Benzimidazole derivative 6

Drug Info

Patented

Solid tumour/cancer

[13]

Bicyclic heteroaryl benzamide derivative 1

Drug Info

Patented

Pruritus

[12]

Bicyclic heteroaryl benzamide derivative 2

Drug Info

Patented

Pruritus

[12]

Bicyclic heteroaryl benzamide derivative 3

Drug Info

Patented

Pruritus

[12]

Bicyclic heteroaryl benzamide derivative 4

Drug Info

Patented

Pruritus

[12]

Bicyclic heteroaryl benzamide derivative 5

Drug Info

Patented

Pruritus

[12]

Bicyclic heteroaryl benzamide derivative 6

Drug Info

Patented

Pruritus

[12]

Bicyclic heteroaryl benzamide derivative 7

Drug Info

Patented

Pruritus

[12]

Bicyclic heteroaryl benzamide derivative 8

Drug Info

Patented

Pruritus

[12]

Bicyclic heteroaryl benzamide derivative 9

Drug Info

Patented

Pruritus

[12]

Five membered heterocyclic benzamide derivative 1

Drug Info

Patented

Pruritus

[12]

Five membered heterocyclic benzamide derivative 2

Drug Info

Patented

Pruritus

[12]

Five membered heterocyclic benzamide derivative 3

Drug Info

Patented

Pruritus

[12]

Imidazo[1,2-b]pyridazine derivative 1

Drug Info

Patented

Solid tumour/cancer

[13]

Imidazo[1,2-b]pyridazine derivative 2

Drug Info

Patented

Solid tumour/cancer

[13]

Imidazo[1,2-b]pyridazine derivative 3

Drug Info

Patented

Solid tumour/cancer

[13]

N-(phenylpyrazolyl)benzamide derivative 1

Drug Info

Patented

Pruritus

[12]

N-acylpiperidine ether derivative 1

Drug Info

Patented

Pruritus

[12]

N-acylpiperidine ether derivative 2

Drug Info

Patented

Pruritus

[12]

N-acylpiperidine ether derivative 4

Drug Info

Patented

Pruritus

[12]

N-acylpiperidine ether derivative 5

Drug Info

Patented

Pruritus

[12]

N-acylpiperidine ether derivative 6

Drug Info

Patented

Pruritus

[12]

N-acylpiperidine ether derivative 7

Drug Info

Patented

Pruritus

[12]

N-acylpyrrolidine ether derivative 2

Drug Info

Patented

Pruritus

[12]

PMID28270021-Compound-WO2010077680 103

Drug Info

Patented

Pruritus

[12]

PMID28270021-Compound-WO2010077680 109

Drug Info

Patented

Pruritus

[12]

PMID28270021-Compound-WO2010077680 201

Drug Info

Patented

Pruritus

[12]

PMID28270021-Compound-WO2010077680 481

Drug Info

Patented

Pruritus

[12]

PMID28270021-Compound-WO2010077680 495

Drug Info

Patented

Pruritus

[12]

PMID28270021-Compound-WO2010077680 803

Drug Info

Patented

Pruritus

[12]

PMID28270021-Compound-WO2010077680 811

Drug Info

Patented

Pruritus

[12]

PMID28270021-Compound-WO2013009582Example16

Drug Info

Patented

Pruritus

[12]

PMID28270021-Compound-WO2013161919Example85-117

Drug Info

Patented

Pruritus

[12]

PMID28270021-Compound-WO2014078408Example1

Drug Info

Patented

Pruritus

[12]

PMID28270021-Compound-WO2014129431Example8-1

Drug Info

Patented

Pruritus

[12]

PMID28270021-Compound-WO2014152663 701

Drug Info

Patented

Osteoarthritis pain

[12]

PMID28270021-Compound-WO2015042088Example4

Drug Info

Patented

Pruritus

[12]

PMID28270021-Compound-WO2016054807Example1

Drug Info

Patented

Pruritus

[12]

PMID28270021-Compound-WO2016054807Example112

Drug Info

Patented

Pruritus

[12]

PMID28270021-Compound-WO2016054807Example71

Drug Info

Patented

Pruritus

[12]

PMID28270021-Compound-WO2016054807Example80

Drug Info

Patented

Pruritus

[12]

PMID28270021-Compound-WO2016054807Example82

Drug Info

Patented

Pruritus

[12]

Pyrazolo[1,5-a]pyridine derivative 1

Drug Info

Patented

Pruritus

[12]

Pyrazolo[4,3-c]pyridine derivative 1

Drug Info

Patented

Pruritus

[12]

Pyrazolo[4,3-h]quinazoline-3-carboxamide derivative 1

Drug Info

Patented

Malignant thymoma

[12]

Pyrido[3,2-d]pyrimidine derivative 2

Drug Info

Patented

Pruritus

[12]

Pyrrolo[2,3-b]pyridine derivative 1

Drug Info

Patented

Pruritus

[12]

Pyrrolo[2,3-b]pyridine derivative 2

Drug Info

Patented

Pruritus

[12]

Pyrrolo[2,3-b]pyridine derivative 3

Drug Info

Patented

Pruritus

[12]

Pyrrolo[2,3-d]pyrimidine derivative 3

Drug Info

Patented

Pruritus

[12]

Pyrrolo[2,3-d]pyrimidine derivative 4

Drug Info

Patented

Pruritus

[12]

Pyrrolo[3,2-c]pyridine derivative 1

Drug Info

Patented

Pruritus

[12]

Six-membered heterocyclic benzamide derivative 2

Drug Info

Patented

Pruritus

[12]

Six-membered heterocyclic benzamide derivative 3

Drug Info

Patented

Pruritus

[12]

Six-membered heterocyclic benzamide derivative 4

Drug Info

Patented

Pruritus

[12]

Six-membered heterocyclic benzamide derivative 6

Drug Info

Patented

Pruritus

[12]

Six-membered heterocyclic benzamide derivative 7

Drug Info

Patented

Pruritus

[12]

Thiadiazolyl carboxamide derivative 1

Drug Info

Patented

Alzheimer disease

[13]

Tri-substituted urea derivative 2

Drug Info

Patented

Pruritus

[12]

Triazolo[4,3-b]pyridazine derivative 2

Drug Info

Patented

Pruritus

[12]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

AZD6918

Drug Info

Discontinued in Phase 1

Advanced solid tumour

[14]

Preclinical Drug(s)

[+] 1 Preclinical Drugs

FX-007

Drug Info

Preclinical

Pain

[15]

Mode of Action

[+] 3 Modes of Action

Inhibitor

[+] 106 Inhibitor drugs

Entrectinib

Drug Info

[2]

Larotrectinib

Drug Info

[1], [16]

Repotrectinib

Drug Info

[4]

CT 327

Drug Info

[18]

SNA-120

Drug Info

[7]

ONO-7579

Drug Info

[3]

Altiratinib

Drug Info

[13]

DS-6051

Drug Info

[19]

LOXO-195

Drug Info

[3]

PLX7486

Drug Info

[3], [20]

3-amino-5-benzyl-substituted indazole derivative 1

Drug Info

[12]

Benzimidazole derivative 6

Drug Info

[13]

Bicyclic heteroaryl benzamide derivative 1

Drug Info

[12]

Bicyclic heteroaryl benzamide derivative 2

Drug Info

[12]

Bicyclic heteroaryl benzamide derivative 3

Drug Info

[12]

Bicyclic heteroaryl benzamide derivative 4

Drug Info

[12]

Bicyclic heteroaryl benzamide derivative 5

Drug Info

[12]

Bicyclic heteroaryl benzamide derivative 6

Drug Info

[12]

Bicyclic heteroaryl benzamide derivative 7

Drug Info

[12]

Bicyclic heteroaryl benzamide derivative 8

Drug Info

[12]

Bicyclic heteroaryl benzamide derivative 9

Drug Info

[12]

Five membered heterocyclic benzamide derivative 1

Drug Info

[12]

Five membered heterocyclic benzamide derivative 2

Drug Info

[12]

Five membered heterocyclic benzamide derivative 3

Drug Info

[12]

Imidazo[1,2-b]pyridazine derivative 1

Drug Info

[13]

Imidazo[1,2-b]pyridazine derivative 2

Drug Info

[13]

Imidazo[1,2-b]pyridazine derivative 3

Drug Info

[13]

Imidazo[1,2-b]pyridazine derivative 4

Drug Info

[13]

Imidazo[1,2-b]pyridazine derivative 5

Drug Info

[13]

Imidazo[1,2-b]pyridazine derivative 7

Drug Info

[13]

N,N-bis(5-pyrazoyl)urea derivative 1

Drug Info

[13]

N-(phenylpyrazolyl)benzamide derivative 1

Drug Info

[12]

N-acylpiperidine ether derivative 1

Drug Info

[12]

N-acylpiperidine ether derivative 2

Drug Info

[12]

N-acylpiperidine ether derivative 4

Drug Info

[12]

N-acylpiperidine ether derivative 5

Drug Info

[12]

N-acylpiperidine ether derivative 6

Drug Info

[12]

N-acylpiperidine ether derivative 7

Drug Info

[12]

N-acylpyrrolidine ether derivative 2

Drug Info

[12]

N-arylmethyl-N-phenyl cyclic urea derivative 1

Drug Info

[13]

N-arylmethyl-N-phenyl cyclic urea derivative 2

Drug Info

[13]

PMID28270010-Compound-Figure16-a

Drug Info

[13]

PMID28270010-Compound-Figure17-1

Drug Info

[13]

PMID28270010-Compound-Figure17-2

Drug Info

[13]

PMID28270010-Compound-Figure17-3

Drug Info

[13]

PMID28270010-Compound-Figure24-b

Drug Info

[13]

PMID28270010-Compound-Figure5-1

Drug Info

[13]

PMID28270010-Compound-Figure5-2

Drug Info

[13]

PMID28270021-Compound-WO2013009582Example16

Drug Info

[12]

PMID28270021-Compound-WO2013161919Example85-117

Drug Info

[12]

PMID28270021-Compound-WO2014078408Example1

Drug Info

[12]

PMID28270021-Compound-WO2014129431Example8-1

Drug Info

[12]

PMID28270021-Compound-WO2014152663 701

Drug Info

[12]

PMID28270021-Compound-WO2015042088Example4

Drug Info

[12]

PMID28270021-Compound-WO2016054807Example1

Drug Info

[12]

PMID28270021-Compound-WO2016054807Example112

Drug Info

[12]

PMID28270021-Compound-WO2016054807Example71

Drug Info

[12]

PMID28270021-Compound-WO2016054807Example80

Drug Info

[12]

PMID28270021-Compound-WO2016054807Example82

Drug Info

[12]

Pyrazolo[1,5-a]pyridine derivative 1

Drug Info

[12]

Pyrazolo[1,5-a]pyrimidine derivative 14

Drug Info

[13]

Pyrazolo[1,5-a]pyrimidine derivative 15

Drug Info

[13]

Pyrazolo[1,5-a]pyrimidine derivative 16

Drug Info

[13]

Pyrazolo[1,5-a]pyrimidine derivative 17

Drug Info

[13]

Pyrazolo[1,5-a]pyrimidine derivative 18

Drug Info

[13]

Pyrazolo[1,5-a]pyrimidine derivative 19

Drug Info

[13]

Pyrazolo[1,5-a]pyrimidine derivative 21

Drug Info

[13]

Pyrazolo[1,5-a]pyrimidine derivative 23

Drug Info

[13]

Pyrazolo[1,5-a]pyrimidine derivative 24

Drug Info

[13]

Pyrazolo[1,5-a]pyrimidine derivative 25

Drug Info

[13]

Pyrazolo[1,5-a]pyrimidine derivative 26

Drug Info

[13]

Pyrazolo[1,5-a]pyrimidine derivative 27

Drug Info

[13]

Pyrazolo[4,3-c]pyridine derivative 1

Drug Info

[12]

Pyrazolo[4,3-h]quinazoline-3-carboxamide derivative 1

Drug Info

[12]

Pyrido[3,2-d]pyrimidine derivative 2

Drug Info

[12]

Pyrrolidinyl urea derivative 10

Drug Info

[13]

Pyrrolidinyl urea derivative 11

Drug Info

[13]

Pyrrolidinyl urea derivative 12

Drug Info

[13]

Pyrrolidinyl urea derivative 2

Drug Info

[13]

Pyrrolidinyl urea derivative 3

Drug Info

[13]

Pyrrolidinyl urea derivative 4

Drug Info

[13]

Pyrrolidinyl urea derivative 5

Drug Info

[13]

Pyrrolidinyl urea derivative 6

Drug Info

[13]

Pyrrolidinyl urea derivative 8

Drug Info

[13]

Pyrrolidinyl urea derivative 9

Drug Info

[13]

Pyrrolo[2,3-b]pyridine derivative 1

Drug Info

[12]

Pyrrolo[2,3-b]pyridine derivative 2

Drug Info

[12]

Pyrrolo[2,3-b]pyridine derivative 3

Drug Info

[12]

Pyrrolo[2,3-d]pyrimidine derivative 3

Drug Info

[12]

Pyrrolo[2,3-d]pyrimidine derivative 4

Drug Info

[12]

Pyrrolo[3,2-c]pyridine derivative 1

Drug Info

[12]

Six-membered heterocyclic benzamide derivative 2

Drug Info

[12]

Six-membered heterocyclic benzamide derivative 3

Drug Info

[12]

Six-membered heterocyclic benzamide derivative 4

Drug Info

[12]

Six-membered heterocyclic benzamide derivative 6

Drug Info

[12]

Six-membered heterocyclic benzamide derivative 7

Drug Info

[12]

Thiadiazolyl carboxamide derivative 1

Drug Info

[13]

Thiazole derivative 4

Drug Info

[13]

Tri-substituted urea derivative 2

Drug Info

[12]

100

Triazolo[4,3-b]pyridazine derivative 2

Drug Info

[12]

101

Ureido-phenyl-substituted triazine derivative 1

Drug Info

[13]

102

AZD6918

Drug Info

[21]

103

FX-007

Drug Info

[22]

104

CEP-5104

Drug Info

[23]

105

CEP-6331

Drug Info

[23]

106

K-252a analogue

Drug Info

[24]

Agonist

[+] 1 Agonist drugs

MIM-D3

Drug Info

[17]

Antagonist

[+] 7 Antagonist drugs

PMID28270021-Compound-WO2010077680 103

Drug Info

[12]

PMID28270021-Compound-WO2010077680 109

Drug Info

[12]

PMID28270021-Compound-WO2010077680 201

Drug Info

[12]

PMID28270021-Compound-WO2010077680 481

Drug Info

[12]

PMID28270021-Compound-WO2010077680 495

Drug Info

[12]

PMID28270021-Compound-WO2010077680 803

Drug Info

[12]

PMID28270021-Compound-WO2010077680 811

Drug Info

[12]

Cell-based Target Expression Variations

Top

Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

Top

Ligand Name: Entrectinib

Ligand Info

Structure Description

THE STRUCTURE OF TRKA KINASE DOMAIN BOUND TO THE INHIBITOR ENTRECTINIB

PDB:5KVT

Method

X-ray diffraction

Resolution

2.45 Å

Mutation

[25]

PDB Sequence

CVHHIKRRDI

⁵¹⁰

VLKWELGEGA

⁵²⁰

FGKVFLAECH

⁵³⁰

NLDKMLVAVK

⁵⁴⁴

ALKEASESAR

⁵⁵⁴

QDFQREAELL

⁵⁶⁴

TMLQHQHIVR

⁵⁷⁴

FFGVCTEGRP

⁵⁸⁴

LLMVFEYMRH

⁵⁹⁴

GDLNRFLRSH

⁶⁰⁴

GPDAKLLAGG

⁶¹⁴

EDVAPGPLGL

⁶²⁴

GQLLAVASQV

⁶³⁴

AAGMVYLAGL

⁶⁴⁴

HFVHRDLATR

⁶⁵⁴

NCLVGQGLVV

⁶⁶⁴

KIGDFGMSRD

⁶⁷⁴

IYSTDYYRVG

⁶⁸⁴

GRTMLPIRWM

⁶⁹⁴

PPESILYRKF

⁷⁰⁴

TTESDVWSFG

⁷¹⁴

VVLWEIFTYG

⁷²⁴

KQPWYQLSNT

⁷³⁴

EAIDCITQGR

⁷⁴⁴

ELERPRACPP

⁷⁵⁴

EVYAIMRGCW

⁷⁶⁴

QREPQQRHSI

⁷⁷⁴

KDVHARLQAL

⁷⁸⁴

AQAHHHH

Residue

Distance (Å)

LEU516

3.361

GLY517

3.777

GLU518

3.286

GLY519

4.922

PHE521

3.916

VAL524

3.184

ALA542

3.335

LYS544

4.576

VAL573

4.062

PHE589

3.591

GLU590

2.872

TYR591

3.886

Residue

Distance (Å)

MET592

3.067

ARG593

3.256

HIS594

4.132

GLY595

3.398

ASP596

3.377

ARG599

3.340

ARG654

3.172

ASN655

3.042

CYS656

3.576

LEU657

3.542

GLY667

3.444

ASP668

3.699

Ligand Name: TPX-0005

Ligand Info

Structure Description

Crystal structure of TrkA (G595R) kinase with repotrectinib

PDB:7VKN

Method

X-ray diffraction

Resolution

2.70 Å

Mutation

Yes

[26]

PDB Sequence

GSGIRVHHIK

⁵⁰⁶

RRDIVLKWEL

⁵¹⁶

GEGAFGKVFL

⁵²⁶

AECHNLLPEQ

⁵³⁶

DKMLVAVKAL

⁵⁴⁶

KEASESARQD

⁵⁵⁶

FQREAELLTM

⁵⁶⁶

LQHQHIVRFF

⁵⁷⁶

GVCTEGRPLL

⁵⁸⁶

MVFEYMRHRD

⁵⁹⁶

LNRFLRSHGP

⁶⁰⁶

DAKLLAGGED

⁶¹⁶

VAPGPLGLGQ

⁶²⁶

LLAVASQVAA

⁶³⁶

GMVYLAGLHF

⁶⁴⁶

VHRDLATRNC

⁶⁵⁶

LVGQGLVVKI

⁶⁶⁶

GDFGMRDIYS

⁶⁷⁷

TDYYRVGGRT

⁶⁸⁷

MLPIRWMPPE

⁶⁹⁷

SILYRKFTTE

⁷⁰⁷

SDVWSFGVVL

⁷¹⁷

WEIFTYGKQP

⁷²⁷

WYQLSNTEAI

⁷³⁷

DCITQGRELE

⁷⁴⁷

RPRACPPEVY

⁷⁵⁷

AIMRGCWQRE

⁷⁶⁷

PQQRHSIKDV

⁷⁷⁷

HARLQALAQA

⁷⁸⁷

PPVYLDV

Residue

Distance (Å)

LEU516

4.035

GLY517

3.681

GLU518

4.372

VAL524

3.795

ALA542

3.087

LYS544

4.277

VAL573

4.178

PHE589

3.930

GLU590

3.183

TYR591

3.820

Residue

Distance (Å)

MET592

3.014

ARG595

3.457

ASP596

3.730

ARG654

3.007

ASN655

2.891

CYS656

3.565

LEU657

3.379

GLY667

3.260

ASP668

3.280

ARG673

3.583

Click to View More Binding Site Information of This Target and Ligand Pair

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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 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 Pathway Affiliation Biological Network Descriptors

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 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 Pathway Affiliation

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Mixed lineage kinase 1 (MAP3K9)	PF00069 ; PF14604	29.808 (93/312)	6.49E-28
Ribosomal protein S6 kinase alpha-3 (RSK3)	PF00069 ; PF00433	28.014 (79/282)	5.87E-21
Fused homolog (STK36)	PF13646 ; PF00069	27.273 (72/264)	6.02E-19
Ribosomal protein S6 kinase alpha-2 (RSK2)	PF00069 ; PF00433	28.185 (73/259)	2.23E-18
Ribosomal protein S6 kinase alpha-6 (RSK6)	PF00069 ; PF00433	28.571 (74/259)	3.34E-18
Ribosomal protein S6 kinase alpha-1 (RSK1)	PF00069 ; PF00433	26.641 (69/259)	4.09E-18
Serine/threonine-protein kinase Nek4 (NEK4)	PF00069	25.095 (66/263)	4.61E-18
MAPK/ERK kinase kinase 3 (MAP3K3)	PF00564 ; PF00069	30.263 (69/228)	2.04E-17
PKC-delta-interacting protein kinase (RIPK4)	PF12796 ; PF00069	27.737 (76/274)	2.73E-17
Aurora kinase B (AURKB)	PF00069	24.606 (78/317)	6.15E-17
Protein kinase C theta (PRKCQ)	PF00130 ; PF00069 ; PF00433 More >>	27.174 (75/276)	6.39E-17
Serine/threonine-protein kinase Nek11 (NEK11)	PF00069	27.957 (78/279)	8.41E-17
Aurora kinase C (AURKC)	PF00069	27.155 (63/232)	1.67E-16
NIMA-related kinase 6 (NEK6)	PF00069	24.727 (68/275)	1.69E-16
Aurora kinase A (AURKA)	PF00069	27.848 (66/237)	2.03E-16
Checkpoint kinase-1 (CHK1)	PF00069	30.909 (68/220)	2.27E-16
NUAK family SNF1-like kinase 2 (NUAK2)	PF00069	24.497 (73/298)	2.37E-16
Serine/threonine-protein kinase Nek5 (NEK5)	PF00069	26.471 (72/272)	5.17E-16
Cyclin-dependent kinase 12 (CDK12)	PF00069	28.696 (66/230)	5.39E-16
Serine/threonine-protein kinase ULK2 (ULK2)	PF12063 ; PF00069	28.326 (66/233)	6.12E-16
Cyclin-dependent kinase 13 (CDK13)	PF12330 ; PF00069	28.322 (81/286)	6.76E-16
Serine/threonine-protein kinase Nek8 (NEK8)	PF00069 ; PF00415	25.926 (70/270)	7.86E-16
Polo-like kinase 2 (PLK2)	PF00069 ; PF00659	22.556 (60/266)	1.08E-15
5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1)	PF16579 ; PF00069	26.923 (77/286)	1.98E-15
MAPK/ERK kinase kinase 4 (MAP3K4)	PF19431 ; PF00069	23.203 (71/306)	1.99E-15
Serine/threonine-protein kinase Nek3 (NEK3)	PF00069	27.068 (72/266)	2.72E-15
NIMA-related kinase 7 (NEK7)	PF00069	22.695 (64/282)	3.20E-15
Serine/threonine-protein kinase Nek9 (NEK9)	PF00069 ; PF00415	25.000 (78/312)	3.27E-15
Cyclin-dependent kinase 15 (CDK15)	PF00069	28.436 (60/211)	4.22E-15
MAPK/ERK kinase kinase 2 (MAP3K2)	PF00564 ; PF00069	26.953 (69/256)	4.43E-15
Serine/threonine-protein kinase 24 (STK24)	PF00069	24.000 (66/275)	4.81E-15
Omphalocele kinase 1 (NUAK1)	PF00069	25.090 (70/279)	5.25E-15
Serine/threonine-protein kinase WNK1 (WNK1)	PF12202 ; PF00069	27.397 (80/292)	7.36E-15
Unc-51 like kinase 3 (ULK3)	PF04212 ; PF00069	25.000 (70/280)	1.90E-14
Serine/threonine-protein kinase 33 (STK33)	PF00069	25.105 (60/239)	1.96E-14
Serine/threonine-protein kinase ICK (CILK1)	PF00069	26.540 (56/211)	2.13E-14
SPS1/STE20-related protein kinase YSK4 (YSK4)	PF00069	25.725 (71/276)	2.20E-14
5'-AMP-activated protein kinase catalytic subunit alpha-2 (PRKAA2)	PF16579 ; PF00069	26.990 (78/289)	2.21E-14
PAK-2 protein kinase (PAK2)	PF00786 ; PF00069	25.188 (67/266)	2.47E-14
Polo-like kinase 4 (PLK4)	PF00069 ; PF18190 ; PF18409 More >>	23.106 (61/264)	2.93E-14
Serine/threonine-protein kinase 26 (STK26)	PF00069	24.597 (61/248)	3.01E-14
Cyclin-dependent kinase 6 (CDK6)	PF00069	29.870 (69/231)	4.09E-14
Serine/threonine-protein kinase 25 (STK25)	PF00069	24.453 (67/274)	4.19E-14
Mitogen-activated protein kinase kinase kinase 15 (MAP3K15)	PF19039 ; PF20309 ; PF20302 ; PF13281 ; PF00069 More >>	25.468 (68/267)	4.26E-14
Cyclin-dependent kinase-like 2 (CDKL2)	PF00069	26.977 (58/215)	6.65E-14
Serine/threonine-protein kinase MARK1 (MARK1)	PF02149 ; PF00069 ; PF00627 More >>	28.111 (61/217)	7.87E-14
Cyclin-dependent kinase 3 (CDK3)	PF00069	28.302 (60/212)	8.36E-14
Maternal embryonic leucine zipper kinase (MELK)	PF02149 ; PF00069	25.979 (73/281)	8.41E-14
SNF-related serine/threonine-protein kinase (SNRK)	PF00069	25.424 (75/295)	9.93E-14
Apoptosis signal-regulating kinase 1 (MAP3K5)	PF19039 ; PF20309 ; PF20302 ; PF13281 ; PF00069 More >>	26.642 (73/274)	1.11E-13
Cyclin-dependent kinase 2 (CDK2)	PF00069	28.505 (61/214)	1.19E-13
NIMA-related kinase 1 (NEK1)	PF00069	26.540 (56/211)	1.59E-13
Microtubule affinity regulating kinase 3 (MARK3)	PF02149 ; PF00069 ; PF00627 More >>	27.442 (59/215)	1.72E-13
Receptor-interacting serine/threonine-protein kinase 3 (RIPK3)	PF00069 ; PF12721	27.491 (80/291)	1.82E-13
Serine/threonine-protein kinase MAK (MAK)	PF00069	26.168 (56/214)	2.26E-13
STE20-related serine/threonine-protein kinase (SLK)	PF00069 ; PF12474	28.837 (62/215)	2.38E-13
Serine/threonine-protein kinase MARK2 (MARK2)	PF02149 ; PF00069 ; PF00627 More >>	28.436 (60/211)	2.81E-13
Apoptosis signal-regulating kinase 2 (MAP3K6)	PF19039 ; PF20309 ; PF20302 ; PF13281 ; PF00069 More >>	28.448 (66/232)	2.98E-13
Serine/threonine-protein kinase ULK1 (ULK1)	PF12063 ; PF00069	25.957 (61/235)	3.08E-13
Testis-specific serine/threonine-protein kinase 1 (TSSK1B)	PF00069	28.244 (74/262)	3.46E-13
Cyclin-dependent kinase-like 4 (CDKL4)	PF00069	25.652 (59/230)	3.62E-13
Dual specificity protein kinase TTK (MPS1)	PF00069	26.115 (82/314)	5.14E-13
IL-1 receptor-associated kinase 1 (IRAK1)	PF00531 ; PF00069	27.273 (60/220)	6.26E-13
WNK lysine-deficient protein kinase 3 (WNK3)	PF12202 ; PF00069	27.305 (77/282)	7.32E-13
Protein kinase N2 (PKN2)	PF02185 ; PF00069 ; PF00433 More >>	28.302 (75/265)	7.93E-13
BR serine/threonine kinase 1 (BRSK1)	PF00069	23.529 (64/272)	9.84E-13
Myosin light chain kinase 2 (MYLK2)	PF00069	22.747 (53/233)	1.11E-12
Inhibitor of nuclear factor kappa-B kinase alpha (IKKA)	PF18397 ; PF12179 ; PF00069 More >>	26.190 (66/252)	1.42E-12
Serine/threonine-protein kinase 3 (STK3)	PF11629 ; PF00069	23.552 (61/259)	1.58E-12
Leucine-rich repeat serine/threonine-protein kinase 1 (LRRK1)	PF12796 ; PF16095 ; PF00069 ; PF08477 More >>	26.531 (65/245)	1.62E-12
Cyclin-dependent kinase-like 3 (CDKL3)	PF00069	26.606 (58/218)	1.68E-12
Testis-specific serine/threonine-protein kinase 4 (TSSK4)	PF00069	26.339 (59/224)	1.86E-12
MST-1 protein kinase (STK4)	PF11629 ; PF00069	24.138 (63/261)	2.06E-12
Cyclin-dependent kinase 4 (CDK4)	PF00069	28.814 (68/236)	2.16E-12
Serine/threonine-protein kinase PAK 6 (PAK6)	PF00786 ; PF00069	25.091 (69/275)	2.49E-12
Oxidative stress responsive 1 (OXSR1)	PF12202 ; PF00069	24.221 (70/289)	2.60E-12
Serine/threonine-protein kinase TAO2 (TAOK2)	PF00069	25.606 (74/289)	3.04E-12
MAP/microtubule affinity-regulating kinase 4 (MARK4)	PF02149 ; PF00069 ; PF00627 More >>	27.230 (58/213)	3.40E-12
Serine/threonine-protein kinase WNK4 (WNK4)	PF12202 ; PF00069	27.055 (79/292)	4.21E-12
Myosin light kinase (MYLK)	PF16620 ; PF00041 ; PF07679 ; PF00069 More >>	24.569 (57/232)	5.06E-12
Cyclin-dependent kinase 14 (CDK14)	PF00069	22.327 (71/318)	5.26E-12
Testis-specific serine kinase 2 (TSSK2)	PF00069	25.974 (80/308)	5.35E-12
Protein kinase C alpha (PRKCA)	PF00130 ; PF00168 ; PF00069 ; PF00433 More >>	24.265 (66/272)	6.40E-12
Salt-inducible kinase 1 (SIK1)	PF00069	25.551 (58/227)	6.92E-12
Cyclin-dependent kinase 5 (CDK5)	PF00069	25.701 (55/214)	7.01E-12
Putative serine/threonine-protein kinase SIK1B (SIK1B)	PF00069	25.551 (58/227)	7.04E-12
Cyclin-dependent kinase 1 (CDK1)	PF00069	25.909 (57/220)	9.13E-12
Salt-inducible kinase 2 (SIK2)	PF00069	26.415 (56/212)	1.10E-11
Serine/threonine-protein kinase WNK2 (WNK2)	PF12202 ; PF00069	26.000 (78/300)	1.24E-11
Protein kinase C delta (PRKCD)	PF00130 ; PF00069 ; PF00433 More >>	26.336 (69/262)	1.29E-11
Serine/threonine-protein kinase NIM1 (NIM1K)	PF00069	24.453 (67/274)	1.36E-11
Myosin light chain kinase 3 (MYLK3)	PF00069	24.561 (56/228)	2.35E-11
PAK-1 protein kinase (PAK1)	PF00786 ; PF00069	23.684 (63/266)	2.73E-11
Cyclin-dependent kinase 18 (CDK18)	PF00069	26.540 (56/211)	2.90E-11
Serine/threonine-protein kinase Sgk1 (SGK1)	PF00069 ; PF00433	23.427 (67/286)	3.83E-11
Cyclin-dependent kinase 17 (CDK17)	PF12330 ; PF00069	25.837 (54/209)	3.97E-11
BR serine/threonine kinase 2 (BRSK2)	PF00069	22.545 (62/275)	5.46E-11
Inhibitor of nuclear factor kappa-B kinase beta (IKKB)	PF18397 ; PF12179 ; PF00069 More >>	25.909 (57/220)	5.54E-11
Serine/threonine-protein kinase 10 (STK10)	PF00069 ; PF12474	27.570 (59/214)	5.78E-11
Protein kinase N1 (PKN1)	PF02185 ; PF00069 ; PF00433 More >>	28.679 (76/265)	6.02E-11
Protein kinase C beta (PRKCB)	PF00130 ; PF00168 ; PF00069 ; PF00433 More >>	25.287 (66/261)	6.97E-11
Cyclin-dependent kinase 16 (CDK16)	PF12330 ; PF00069	25.472 (54/212)	7.25E-11
Mitogen-activated protein kinase 15 (MAPK15)	PF00069	28.448 (66/232)	7.55E-11
Serine/threonine-protein kinase PAK 3 (PAK3)	PF00786 ; PF00069	23.684 (63/266)	8.37E-11
Polo-like kinase 1 (PLK1)	PF00069 ; PF00659	22.963 (62/270)	8.98E-11
NIMA-related kinase 2 (NEK2)	PF00069	24.908 (68/273)	9.56E-11
Death-associated protein kinase 1 (DAPK1)	PF00023 ; PF12796 ; PF13637 ; PF00531 ; PF00069 More >>	23.297 (65/279)	1.04E-10
Bone morphogenetic protein receptor (BMPR2)	PF01064 ; PF00069	25.000 (81/324)	1.42E-10
ERK activator kinase 5 (MAP2K5)	PF00564 ; PF00069	25.271 (70/277)	1.47E-10
MEK kinase kinase 1 (MAP4K1)	PF00780 ; PF00069	26.540 (56/211)	1.53E-10
Cyclin-dependent kinase 20 (CDK20)	PF00069	27.358 (58/212)	1.69E-10
Putative 3-phosphoinositide-dependent protein kinase 2 (PDPK2P)	PF00069	19.512 (40/205)	1.74E-10
Serine/threonine-protein kinase PLK3 (PLK3)	PF00069 ; PF00659	24.675 (57/231)	1.78E-10
TAO kinase 1 (TAOK1)	PF00069	26.117 (76/291)	1.92E-10
Cyclin-dependent kinase-like 1 (CDKL1)	PF00069	25.455 (56/220)	2.04E-10
ERK activator kinase 1 (MEK1)	PF00069	27.074 (62/229)	2.53E-10
Cyclin-dependent kinase 9 (CDK9)	PF00069	26.316 (65/247)	2.72E-10
MAPK/ERK kinase kinase 1 (MAP3K1)	PF00069	24.545 (54/220)	2.72E-10
Serine/threonine-protein kinase tousled-like 2 (TLK2)	PF00069	24.265 (66/272)	2.95E-10
Proto-oncogene serine/threonine-protein kinase mos (MOS)	PF00069	26.293 (61/232)	3.27E-10
Serine/threonine-protein kinase PAK 5 (PAK5)	PF00786 ; PF00069	23.792 (64/269)	3.81E-10
Homeodomain-interacting protein kinase 1 (HIPK1)	PF00069	30.493 (68/223)	4.15E-10
Microtubule-associated serine/threonine-protein kinase 3 (MAST3)	PF08926 ; PF17820 ; PF02163 ; PF00069 More >>	24.806 (64/258)	4.16E-10
Calcium/calmodulin-dependent protein kinase type 1 (CAMK1)	PF00069	24.453 (67/274)	4.50E-10
PAK-4 protein kinase (PAK4)	PF00786 ; PF00069	23.019 (61/265)	4.71E-10
Tyrosine-protein kinase EIF2AK2 (p68)	PF00035 ; PF00069	27.511 (63/229)	5.25E-10
cAMP-dependent protein kinase catalytic subunit alpha (PRKACA)	PF00069	23.507 (63/268)	5.70E-10
Phosphoinositide dependent protein kinase-1 (PDPK1)	PF14593 ; PF00069	19.512 (40/205)	5.92E-10
Serine/threonine-protein kinase NLK (NLK)	PF00069	24.691 (60/243)	6.39E-10
cAMP-dependent protein kinase catalytic subunit beta (PRKACB)	PF00069	23.358 (64/274)	7.32E-10
Protein kinase C gamma (PRKCG)	PF00130 ; PF00168 ; PF00069 ; PF00433 More >>	24.812 (66/266)	7.69E-10
Cyclin-dependent kinase-like 5 (CDKL5)	PF00069	24.658 (54/219)	9.72E-10
Calcium/calmodulin-dependent protein kinase type 1G (CAMK1G)	PF00069	24.314 (62/255)	1.10E-09
Serine/threonine-protein kinase H2 (PSKH2)	PF00069	24.696 (61/247)	1.11E-09
Putative serine/threonine-protein kinase PRKY (PRKY)	PF00069	22.936 (50/218)	1.19E-09
IL-1 receptor-associated kinase 3 (IRAK3)	PF00531 ; PF00069	24.336 (55/226)	1.25E-09
Serine/threonine-protein kinase tousled-like 1 (TLK1)	PF00069	25.100 (63/251)	1.38E-09
SIK family kinase 3 (SIK3)	PF00069	25.000 (54/216)	1.41E-09
TGF-beta receptor type I (TGFBR1)	PF01064 ; PF00069 ; PF08515 More >>	25.982 (86/331)	1.49E-09
Ste-20-related kinase (STK39)	PF12202 ; PF00069	25.446 (57/224)	1.76E-09
Inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE)	PF00069 ; PF18394 ; PF18396 More >>	30.303 (70/231)	1.94E-09
Cyclin-dependent kinase 11B (CDK11B)	PF00069	25.000 (53/212)	2.00E-09
Calmodulin-dependent kinase II (CAMKK2)	PF00069	26.104 (65/249)	2.35E-09
Calcium/calmodulin-dependent protein kinase type 1D (CAMK1D)	PF00069	24.088 (66/274)	2.65E-09
Cyclin-dependent kinase 11A (CDK11A)	PF00069	24.775 (55/222)	3.10E-09
cAMP-dependent protein kinase catalytic subunit gamma (PRKACG)	PF00069	27.778 (40/144)	3.15E-09
Ribosomal protein S6 kinase beta-2 (RPS6KB2)	PF00069 ; PF00433	22.642 (60/265)	3.24E-09
Microtubule-associated serine/threonine-protein kinase 2 (MAST2)	PF08926 ; PF17820 ; PF00069 More >>	22.909 (63/275)	3.80E-09
Peripheral plasma membrane protein CASK (CASK)	PF00625 ; PF02828 ; PF00595 ; PF00069 ; PF00018 More >>	27.459 (67/244)	3.96E-09
Microtubule-associated serine/threonine-protein kinase 4 (MAST4)	PF08926 ; PF17820 ; PF02163 ; PF00069 More >>	23.377 (54/231)	4.92E-09
Cyclin-dependent kinase 7 (CDK7)	PF00069	24.413 (52/213)	5.05E-09
MEK kinase kinase 3 (MAP4K3)	PF00780 ; PF00069	24.481 (59/241)	7.35E-09
Stress-activated protein kinase 2a (p38 alpha)	PF00069	25.346 (55/217)	8.21E-09
RAC-beta serine/threonine-protein kinase (AKT2)	PF00169 ; PF00069 ; PF00433 More >>	23.596 (63/267)	9.17E-09
cAMP-dependent protein kinase catalytic subunit PRKX (PRKX)	PF00069	22.018 (48/218)	9.37E-09
ERK activator kinase 2 (MEK2)	PF00069	28.139 (65/231)	9.91E-09
Striated muscle preferentially expressed protein kinase (SPEG)	PF07679 ; PF00069 ; PF16650 More >>	25.862 (60/232)	9.96E-09
Cyclin-dependent kinase 10 (CDK10)	PF00069	27.273 (72/264)	1.02E-08
Myosin light chain kinase family member 4 (MYLK4)	PF00069	21.983 (51/232)	1.09E-08
Serine/threonine-protein kinase STK11 (STK11)	PF00069	25.000 (71/284)	1.21E-08
Serine/threonine-protein kinase SBK1 (SBK1)	PF00069	25.806 (72/279)	1.27E-08
TAO kinase 3 (TAOK3)	PF00069	26.271 (62/236)	1.30E-08
Protein kinase G1 (PRKG1)	PF00027 ; PF16808 ; PF00069 More >>	21.404 (61/285)	1.33E-08
Serine/threonine-protein kinase cot (COT)	PF00069	23.741 (66/278)	1.98E-08
Mitogen-activated protein kinase kinase kinase kinase 5 (MAP4K5)	PF00780 ; PF00069	25.229 (55/218)	2.13E-08
MAPK/MAK/MRK overlapping kinase (MOK)	PF00069	27.830 (59/212)	2.41E-08
Microtubule-associated serine/threonine-protein kinase 1 (MAST1)	PF08926 ; PF17820 ; PF00069 More >>	23.377 (54/231)	2.43E-08
Extracellular signal-regulated kinase 1 (ERK1)	PF00069	25.296 (64/253)	2.67E-08
Extracellular signal-regulated kinase 2 (ERK2)	PF00069	24.651 (53/215)	2.83E-08
Myosin-IIIa (MYO3A)	PF00612 ; PF00063 ; PF00069 More >>	24.555 (69/281)	2.94E-08
Extracellular signal-regulated kinase 5 (ERK5)	PF00069	26.147 (57/218)	3.31E-08
Homeodomain interacting protein kinase 2 (HIPK2)	PF00069	29.596 (66/223)	3.83E-08
Homeodomain-interacting protein kinase 3 (HIPK3)	PF00069	28.372 (61/215)	4.15E-08
Hormonally up-regulated neu tumor-associated kinase (HUNK)	PF00069	24.057 (51/212)	4.33E-08
Serine/threonine-protein kinase greatwall (MASTL)	PF00069	25.773 (50/194)	4.46E-08
Ribosomal protein S6 kinase beta-1 (S6K1)	PF00069 ; PF00433	23.462 (61/260)	5.05E-08
RAC-alpha serine/threonine-protein kinase (AKT1)	PF00169 ; PF00069 ; PF00433 More >>	24.254 (65/268)	5.23E-08
Serine/threonine-protein kinase 32C (STK32C)	PF00069	22.662 (63/278)	5.32E-08
RAC-gamma serine/threonine-protein kinase (AKT3)	PF00169 ; PF00069 ; PF00433 More >>	23.675 (67/283)	5.45E-08
CDC42 binding protein kinase alpha (DMPK-like alpha)	PF00130 ; PF00780 ; PF08826 ; PF15796 ; PF00069 ; PF00433 More >>	24.096 (60/249)	6.48E-08
Myosin-IIIb (MYO3B)	PF00612 ; PF00063 ; PF00069 More >>	26.991 (61/226)	6.99E-08
Serine/threonine-protein kinase H1 (PSKH1)	PF00069	23.305 (55/236)	7.65E-08
Protein kinase G2 (PRKG2)	PF00027 ; PF00069	22.472 (60/267)	9.38E-08
Serine/threonine-protein kinase Sgk3 (SGK3)	PF00069 ; PF00433 ; PF00787 More >>	23.958 (69/288)	1.01E-07
Serine/threonine-protein kinase 32A (STK32A)	PF00069	20.974 (56/267)	1.02E-07
Calcium/calmodulin-dependent protein kinase type 1B (PNCK)	PF00069	24.638 (68/276)	1.17E-07
Serine/threonine-protein kinase MRCK beta (CDC42BPB)	PF00130 ; PF00780 ; PF08826 ; PF15796 ; PF00069 More >>	25.296 (64/253)	1.22E-07
Mitogen-activated protein kinase 4 (MAPK4)	PF00069	27.136 (54/199)	1.43E-07
Activin receptor type IB (ACVR1B)	PF01064 ; PF00069 ; PF08515 More >>	26.563 (68/256)	1.57E-07
Rho-associated protein kinase 1 (ROCK1)	PF00069 ; PF08912	25.630 (61/238)	1.74E-07
Mitogen-activated protein kinase 6 (MAPK6)	PF00069	27.111 (61/225)	1.82E-07
Anti-mullerian hormone II receptor (AMHR2)	PF00069	24.773 (82/331)	1.99E-07
Serine/threonine-protein kinase 17B (STK17B)	PF00069	23.750 (57/240)	2.04E-07
Eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1)	PF00069	29.091 (48/165)	2.14E-07
MAP kinase p38 (MAPK12)	PF00069	25.397 (64/252)	2.19E-07
CaM-kinase IV kinase (CAMKK1)	PF00069	28.571 (50/175)	2.24E-07
Calcium/calmodulin-dependent protein kinase type II subunit alpha (CAMK2A)	PF08332 ; PF00069	24.775 (55/222)	2.27E-07
Calcium/calmodulin-dependent protein kinase type II subunit beta (CAMK2B)	PF08332 ; PF00069	25.112 (56/223)	2.33E-07
Interleukin-1 receptor-associated kinase-like 2 (IRAK2)	PF00531 ; PF00069	24.186 (52/215)	2.55E-07
Doublecortin-like kinase 3 (DCLK3)	PF00069	22.170 (47/212)	3.78E-07
Calcium/calmodulin-dependent protein kinase type II subunit gamma (CAMK2G)	PF08332 ; PF00069	25.000 (57/228)	3.91E-07
Yet another novel kinase 2 (STK32B)	PF00069	22.222 (62/279)	4.16E-07
Protein kinase C epsilon (PRKCE)	PF00130 ; PF00168 ; PF00069 ; PF00433 More >>	22.388 (60/268)	7.52E-07
Tau-tubulin kinase (TTBK1)	PF00069	24.314 (62/255)	7.53E-07
Serine/threonine-protein kinase Sgk2 (SGK2)	PF00069 ; PF00433	24.681 (58/235)	7.96E-07
Death-associated protein kinase 2 (DAPK2)	PF00069	21.849 (52/238)	7.97E-07
Hemicentin-2 (HMCN2)	PF12662 ; PF07645 ; PF07474 ; PF07679 ; PF13927 More >>	25.128 (49/195)	8.40E-07
Testis-specific serine/threonine-protein kinase 6 (TSSK6)	PF00069	27.778 (60/216)	8.73E-07
Mitogen-activated protein kinase 13 (MAPK13)	PF00069	26.291 (56/213)	8.79E-07
Activin receptor type IIA (ACVR2A)	PF01064 ; PF00069	25.217 (58/230)	9.02E-07
Nik-related protein kinase (NRK)	PF00780 ; PF00069	25.210 (60/238)	9.75E-07
Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D)	PF08332 ; PF00069	25.688 (56/218)	1.04E-06
MEK kinase kinase 2 (MAP4K2)	PF00780 ; PF00069	24.880 (52/209)	1.07E-06
Death-associated protein kinase 3 (DAPK3)	PF00069	22.747 (53/233)	1.18E-06
Doublecortin-like kinase 1 (DCLK1)	PF03607 ; PF00069	24.155 (50/207)	1.74E-06
Hemicentin-1 (HMCN1)	PF12662 ; PF07645 ; PF07474 ; PF07679 ; PF13927 ; PF00090 More >>	27.624 (50/181)	1.84E-06
Misshapen-like kinase 1 (MINK1)	PF00780 ; PF00069	22.831 (50/219)	1.89E-06
MAPK-activated protein kinase 2 (MAPKAPK2)	PF00069	23.208 (68/293)	1.98E-06
Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4)	PF00069	23.188 (64/276)	1.99E-06
Serine/threonine-protein kinase pim-2 (PIM2)	PF00069	26.250 (42/160)	2.34E-06
Serine/threonine-protein kinase Nek10 (NEK10)	PF00069	24.434 (54/221)	2.50E-06
Stress-activated protein kinase 2b (p38 beta)	PF00069	24.771 (54/218)	2.72E-06
Doublecortin-like kinase 2 (DCLK2)	PF03607 ; PF00069	24.066 (58/241)	2.75E-06
Titin (TTN)		24.670 (56/227)	2.88E-06
Phosphorylase kinase testis gamma 2 (PHKG2)	PF00069	22.549 (46/204)	3.02E-06
PAS domain-containing serine/threonine-protein kinase (PASK)	PF13426 ; PF00069	21.942 (61/278)	3.95E-06
Rho-associated protein kinase 2 (ROCK2)	PF00069 ; PF08912	25.339 (56/221)	4.75E-06
TGF-beta-stimulated factor 1 (STK16)	PF00069	22.951 (70/305)	5.63E-06
Dual-specificity tyrosine-phosphorylation regulated kinase 1B (DYRK1B)	PF00069	26.522 (61/230)	5.70E-06
Serine/threonine-protein kinase LATS1 (LATS1)	PF00069 ; PF00627	22.989 (60/261)	7.31E-06
Dual-specificity tyrosine-phosphorylation regulated kinase 3 (DYRK3)	PF00069	22.785 (54/237)	8.34E-06
MAP kinase signal-integrating kinase 2 (MKNK2)	PF00069	27.074 (62/229)	8.94E-06
Ribosomal protein S6 kinase alpha-4 (RPS6KA4)	PF00069 ; PF00433	23.897 (65/272)	9.34E-06
Testis-specific serine/threonine-protein kinase 3 (TSSK3)	PF00069	24.402 (51/209)	9.90E-06
Serine/threonine-protein kinase NIK (MAP3K14)	PF00069	24.828 (72/290)	1.04E-05
PDZ binding kinase (PBK)	PF00069	27.568 (51/185)	1.33E-05
TRAF2 and NCK interacting kinase (TNIK)	PF00780 ; PF00069	21.005 (46/219)	1.44E-05
Cyclin-G-associated kinase (GAK)	PF00069 ; PF10409	22.635 (67/296)	1.51E-05
Protein kinase N3 (PKN3)	PF02185 ; PF00069 ; PF00433 More >>	27.778 (65/234)	1.54E-05
MEK kinase kinase 4 (MAP4K4)	PF00780 ; PF00069	21.918 (48/219)	1.91E-05
Myotonin-protein kinase (DMPK)	PF08826 ; PF00069	21.825 (55/252)	1.94E-05
G protein-coupled receptor kinase 4 (GRK4)	PF00069 ; PF00615	22.269 (53/238)	1.97E-05
Homeodomain-interacting protein kinase 4 (HIPK4)	PF00069	26.636 (57/214)	2.06E-05
Ribosomal protein S6 kinase-related protein (RSKR)	PF00069	30.612 (30/98)	2.27E-05
Dual specificity mitogen-activated protein kinase kinase 3 (MAP2K3)	PF00069	26.891 (64/238)	2.71E-05
Serine/threonine-protein kinase D2 (PRKD2)	PF00130 ; PF00069	24.409 (62/254)	2.84E-05
Serine/threonine-protein kinase D3 (PRKD3)	PF00130 ; PF00169 ; PF00069 More >>	24.806 (64/258)	2.87E-05
Tau-tubulin kinase 2 (TTBK2)	PF00069	21.862 (54/247)	2.90E-05
NF-kappa-B-activating kinase (TBK1)	PF00069 ; PF18394 ; PF18396 More >>	25.483 (66/259)	3.27E-05
Beta-adrenergic receptor kinase 1 (ADRBK1)	PF00169 ; PF00069 ; PF00615 More >>	23.438 (45/192)	3.53E-05
ERK activator kinase 7 (MAP2K7)	PF00069	24.775 (55/222)	3.79E-05
TBC domain-containing protein kinase-like protein (TBCK)	PF00069 ; PF00566 ; PF00581 More >>	23.762 (48/202)	4.11E-05
Stress-activated protein kinase JNK2 (JNK2)	PF00069	25.381 (50/197)	4.91E-05
G protein-coupled receptor kinase 5 (GRK5)	PF00069 ; PF00615	24.537 (53/216)	5.20E-05
Protein kinase D (PRKD1)	PF00130 ; PF00169 ; PF00069 More >>	23.622 (60/254)	6.06E-05
Beta-adrenergic receptor kinase 2 (ADRBK2)	PF00169 ; PF00069 ; PF00615 More >>	22.513 (43/191)	6.15E-05
Contactin-1 (CNTN1)	PF00041 ; PF07679 ; PF13927 More >>	25.500 (51/200)	7.55E-05
Protein kinase C eta type (PRKCH)	PF00130 ; PF00168 ; PF00069 ; PF00433 More >>	21.456 (56/261)	8.21E-05
Wee1-like protein kinase (WEE1)	PF00069	22.064 (62/281)	8.40E-05
Obscurin (OBSCN)	PF00041 ; PF07679 ; PF00612 ; PF00069 ; PF00621 More >>	22.222 (60/270)	8.52E-05
Protein kinase C iota (PRKCI)	PF00130 ; PF00564 ; PF00069 ; PF00433 More >>	20.000 (56/280)	8.88E-05
Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6)	PF00069	23.922 (61/255)	9.05E-05
G protein-coupled receptor kinase 6 (GRK6)	PF00069 ; PF00615	25.532 (36/141)	1.11E-04
PIM-3 protein kinase (PIM3)	PF00069	28.667 (43/150)	1.17E-04
Stress-activated protein kinase JNK3 (JNK3)	PF00069	24.365 (48/197)	1.22E-04
Stress-activated protein kinase JNK1 (JNK1)	PF00069	24.775 (55/222)	1.39E-04
PRKR-like endoplasmic reticulum kinase (PERK)	PF00069	26.119 (35/134)	1.58E-04
Serine/threonine-protein kinase/endoribonuclease IRE2 (ERN2)	PF00069 ; PF06479	26.596 (50/188)	1.72E-04
Large tumor suppressor homolog 2 (LATS2)	PF00069 ; PF00433	22.878 (62/271)	1.87E-04
Serine/threonine-protein kinase ULK4 (ULK4)	PF00069	23.077 (39/169)	1.92E-04
Neogenin (NEO1)	PF00041 ; PF07679 ; PF13895 ; PF13927 ; PF06583 More >>	24.157 (43/178)	1.92E-04
Ribosomal protein S6 kinase alpha-5 (RSK5)	PF00069 ; PF00433	22.939 (64/279)	1.99E-04
Cytoplasmic DRAK1 (STK17A)	PF00069	28.319 (32/113)	2.02E-04
Triple functional domain protein (TRIO)	PF00650 ; PF07679 ; PF00169 ; PF00069 ; PF00621 ; PF16609 ; PF00018 ; PF00435 More >>	28.926 (35/121)	3.13E-04
Serine/threonine-protein kinase 35 (STK35)	PF00069	22.353 (38/170)	3.62E-04
Serine/threonine kinase-like domain-containing protein STKLD1 (STKLD1)	PF00069	29.787 (28/94)	3.72E-04
Casein kinase I epsilon (CSNK1E)	PF00069	23.984 (59/246)	4.12E-04
Citron Rho-interacting kinase (CIT)	PF00780 ; PF00169 ; PF00069 More >>	24.186 (52/215)	4.68E-04
NDR2 protein kinase (STK38L)	PF00069 ; PF00433	19.495 (54/277)	5.21E-04
Activin receptor type IIB (ACVR2B)	PF01064 ; PF00069	21.368 (50/234)	5.80E-04
Serine/threonine-protein kinase MRCK gamma (CDC42BPG)	PF00130 ; PF00780 ; PF08826 ; PF00069 More >>	22.568 (58/257)	7.39E-04
BMP-2-inducible protein kinase (BMP2K)	PF15282 ; PF00069	22.500 (54/240)	8.14E-04
Serine/threonine-protein kinase PRP4 homolog (PRPF4B)	PF00069	23.474 (50/213)	1.00E-03
Netrin receptor DCC (DCC)	PF00041 ; PF07679 ; PF06583 More >>	25.683 (47/183)	1.00E-03
Casein kinase I delta (CSNK1D)	PF00069	23.577 (58/246)	1.00E-03
CDC-like kinase 4 (CLK4)	PF00069	25.941 (62/239)	2.00E-03
Limbic system-associated membrane protein (LSAMP)	PF07679 ; PF13927	26.042 (50/192)	2.00E-03
Leucine-rich repeat and fibronectin type-III domain-containing protein 5 (LRFN5)	PF07679 ; PF13306	23.529 (52/221)	2.00E-03
Neuronal growth regulator 1 (NEGR1)	PF07679 ; PF13927	27.411 (54/197)	2.00E-03
Neural cell adhesion molecule 1 (NCAM1)	PF00041 ; PF07679 ; PF13927 More >>	24.000 (48/200)	3.00E-03
NDR1 protein kinase (STK38)	PF00069 ; PF00433	19.134 (53/277)	3.00E-03
Serine/threonine-protein kinase PDIK1L (PDIK1L)	PF00069	20.126 (32/159)	3.00E-03
Phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform (PHKG1)	PF00069	22.488 (47/209)	4.00E-03
MAPK-activated protein kinase 3 (MAPKAPK3)	PF00069	23.871 (37/155)	4.00E-03
Membrane-associated kinase (PKMYT1)	PF00069	23.922 (61/255)	4.00E-03
Endoplasmic reticulum to nucleus signaling 1 (ERN1)	PF00069 ; PF06479	24.670 (56/227)	5.00E-03
Calcium/calmodulin-dependent protein kinase type IV (CAMK4)	PF00069	22.500 (54/240)	5.00E-03
Click to Show/Hide the Information of Human Similarity Proteins

KEGG Pathway	Pathway ID	Affiliated Target
MAPK signaling pathway	hsa04010	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Ras signaling pathway	hsa04014	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Calcium signaling pathway	hsa04020	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
PI3K-Akt signaling pathway	hsa04151	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Apoptosis	hsa04210	Affiliated Target
Class: Cellular Processes => Cell growth and death	Pathway Hierarchy
Neurotrophin signaling pathway	hsa04722	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Inflammatory mediator regulation of TRP channels	hsa04750	Affiliated Target
Class: Organismal Systems => Sensory system	Pathway Hierarchy
Click to Show/Hide the Information of Affiliated Human Pathways

Degree	41	Degree centrality	4.40E-03	Betweenness centrality	2.17E-03
Closeness centrality	2.47E-01	Radiality	1.43E+01	Clustering coefficient	1.12E-01
Neighborhood connectivity	3.14E+01	Topological coefficient	5.60E-02	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-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Drug Resistance
Mutation (DRM)

Drug Resistance Mutation Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 9 KEGG Pathways

MAPK signaling pathway

Endocytosis

Apoptosis

Neurotrophin signaling pathway

Inflammatory mediator regulation of TRP channels

Pathways in cancer

Transcriptional misregulation in cancer

Thyroid cancer

Central carbon metabolism in cancer

NetPath Pathway

[+] 1 NetPath Pathways

IL2 Signaling Pathway

PID Pathway

[+] 1 PID Pathways

Neurotrophic factor-mediated Trk receptor signaling

Reactome

[+] 4 Reactome Pathways

Frs2-mediated activation

ARMS-mediated activation

NGF-independant TRKA activation

PI3K/AKT activation

WikiPathways

[+] 4 WikiPathways

MAPK Signaling Pathway

BDNF signaling pathway

Integrated Pancreatic Cancer Pathway

NGF signalling via TRKA from the plasma membrane

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.

REF 2

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019

REF 3

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

REF 4

FDA Approved Drug Products from FDA Official Website. 2023. Application Number: 218213

REF 5

ClinicalTrials.gov (NCT01960010) A Safety and Efficacy Study of MIM-D3 Ophthalmic Solution for the Treatment of Dry Eye. U.S. National Institutes of Health.

REF 6

ClinicalTrials.gov (NCT01808157) A Study to Evaluate the Efficacy, Safety and Tolerability of CT327 in Atopic Dermatitis. U.S. National Institutes of Health.

REF 7

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

REF 8

ClinicalTrials.gov (NCT03556228) Oral TrkA Inhibitor VMD-928 for Treatment of Advanced Adult Solid Tumors or Lymphoma. U.S. National Institutes of Health.

REF 9

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800040094)

REF 10

ClinicalTrials.gov (NCT02279433) A First-in-human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of DS-6051b. U.S. National Institutes of Health.

REF 11

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800038879)

REF 12

Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part II.Expert Opin Ther Pat. 2017 Jul;27(7):831-849.

REF 13

Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part I.Expert Opin Ther Pat. 2017 Jun;27(6):733-751.

REF 14

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800028850)

REF 15

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800037108)

REF 16

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

REF 17

Safety and efficacy of MIM-D3 ophthalmic solutions in a randomized, placebo-controlled Phase 2 clinical trial in patients with dry eye. Clin Ophthalmol. 2013; 7: 1275-1285.

REF 18

Topical TrkA Kinase Inhibitor CT327 is an Effective, Novel Therapy for the Treatment of Pruritus due to Psoriasis: Results from Experimental Studies, and Efficacy and Safety of CT327 in a Phase 2b Clinical Trial in Patients with Psoriasis. Acta Derm Venereol. 2015 May;95(5):542-8.

REF 19

National Cancer Institute Drug Dictionary (drug id 766123).

REF 20

National Cancer Institute Drug Dictionary (drug id 747694).

REF 21

Clinical pipeline report, company report or official report of AstraZeneca (2009).

REF 22

Preclinical trail of FX007 for treating osteoarthritis. Flexion Therapeutics Inc.

REF 23

Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-linea... J Med Chem. 2008 Sep 25;51(18):5680-9.

REF 24

Synthesis, modeling, and in vitro activity of (3'S)-epi-K-252a analogues. Elucidating the stereochemical requirements of the 3'-sugar alcohol on tr... J Med Chem. 2005 Jun 2;48(11):3776-83.

REF 25

Antitumor Activity and Safety of the Pan-TRK, ROS1, and ALK inhibitor Entrectinib (RXDX-101): Combined Results from Two Phase I Trials

REF 26

Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations. Mol Cancer Ther. 2021 Dec;20(12):2446-2456.

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