Binding Site Information of Target

Target General Information

Target ID

T51076

Target Info

Target Name

NT-3 growth factor receptor (TrkC)

Synonyms

TrkC tyrosine kinase; Trk-C; TRKC; Neurotrophic tyrosine kinase receptor type 3; NT3 growth factor receptor; GP145TrkC; GP145-TrkC

Target Type

Successful Target

Gene Name

NTRK3

Biochemical Class

Kinase

UniProt ID

NTRK3_HUMAN

Drug Binding Sites of Target

Top

Ligand Name: L-serine-O-phosphate

Ligand Info

Structure Description

(R)-2-Phenylpyrrolidine Substitute Imidazopyridazines: a New Class of Potent and Selective Pan-TRK Inhibitors

PDB:4YMJ

Method

X-ray diffraction

Resolution

2.00 Å

Mutation

[1]

PDB Sequence

GIHVQHIKRR

⁵³⁶

DIVLKRELGE

⁵⁴⁶

GAFGKVFLAE

⁵⁵⁶

CYNLSPTKDK

⁵⁶⁶

MLVAVKALKD

⁵⁷⁶

PTLAARKDFQ

⁵⁸⁶

REAELLTNLQ

⁵⁹⁶

HEHIVKFYGV

⁶⁰⁶

CGDGDPLIMV

⁶¹⁶

FEYMKHGDLN

⁶²⁶

KFLRAHGPGE

⁶⁵⁰

LGLSQMLHIA

⁶⁶⁰

SQIASGMVYL

⁶⁷⁰

ASQHFVHRDL

⁶⁸⁰

ATRNCLVGAN

⁶⁹⁰

LLVKIGDFGD

⁷⁰³

VYTDYYRHTM

⁷³¹

LPIRWMPPES

⁷⁴¹

IMYRKFTTES

⁷⁵¹

DVWSFGVILW

⁷⁶¹

EIFTYGKQPW

⁷⁷¹

FQLSNTEVIE

⁷⁸¹

CITQGRVLER

⁷⁹¹

PRVCPKEVYD

⁸⁰¹

VMLGCWQREP

⁸¹¹

QQRLNIKEIY

⁸²¹

KILHALGKAT

⁸³¹

Residue

Distance (Å)

ASP703

3.465

VAL704

3.541

TYR705

1.330

Residue

Distance (Å)

THR707

1.328

ASP708

2.986

TYR709

3.109

Ligand Name: 3-[2-[6-(4-aminophenyl)imidazo[1,2-a]pyrazin-3-yl]ethynyl]-2-methyl-N-[3-(4-methylpiperazin-1-yl)-5-propan-2-ylphenyl]benzamide

Ligand Info

Structure Description

Crystal structure of TRKc in complex with 3-((6-(4-aminophenyl)imidazo[1,2-a]pyrazin-3-yl)ethynyl)- N-(3-isopropyl-5-((4-methylpiperazin-1-yl)methyl)phenyl)-2- methylbenzamide

PDB:6KZD

Method

X-ray diffraction

Resolution

1.71 Å

Mutation

[2]

PDB Sequence

TYVQHIKRRD

⁵³⁷

IVLKRELGEG

⁵⁴⁷

AFGKVFLAEC

⁵⁵⁷

YNLSPTKDKM

⁵⁶⁷

LVAVKALKDP

⁵⁷⁷

TLAARKDFQR

⁵⁸⁷

EAELLTNLQH

⁵⁹⁷

EHIVKFYGVC

⁶⁰⁷

GDGDPLIMVF

⁶¹⁷

EYMKHGDLNK

⁶²⁷

FLRAHGPDAG

⁶⁴⁹

ELGLSQMLHI

⁶⁵⁹

ASQIASGMVY

⁶⁶⁹

LASQHFVHRD

⁶⁷⁹

LATRNCLVGA

⁶⁸⁹

NLLVKIGDFG

⁶⁹⁹

MSRDVYSTDY

⁷⁰⁹

YRLHTMLPIR

⁷³⁵

WMPPESIMYR

⁷⁴⁵

KFTTESDVWS

⁷⁵⁵

FGVILWEIFT

⁷⁶⁵

YGKQPWFQLS

⁷⁷⁵

NTEVIECITQ

⁷⁸⁵

GRVLERPRVC

⁷⁹⁵

PKEVYDVMLG

⁸⁰⁵

CWQREPQQRL

⁸¹⁵

NIKEIYKILH

⁸²⁵

ALGKATPIYL

⁸³⁵

Residue

Distance (Å)

LEU544

4.111

VAL552

3.895

ALA570

3.178

LYS572

3.561

GLU588

2.650

LEU591

3.684

LEU592

3.627

LEU595

3.526

ILE600

4.444

VAL601

3.633

PHE617

3.730

GLU618

2.914

TYR619

3.509

MET620

2.856

Residue

Distance (Å)

GLY623

3.593

ASP624

3.797

LYS627

4.800

LEU670

4.865

PHE675

4.072

HIS677

3.647

ARG678

4.280

ARG683

4.921

LEU686

3.607

ILE695

4.360

GLY696

3.363

ASP697

2.807

PHE698

3.422

Ligand Name: 3-(2-imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methyl-N-[3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]benzamide

Ligand Info

Structure Description

crystal structure of TRKc in complex with 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methyl-N-(3-((4- methylpiperazin-1-yl)methyl)-5- (trifluoromethyl)phenyl)benzamide

PDB:6KZC

Method

X-ray diffraction

Resolution

2.00 Å

Mutation

[2]

PDB Sequence

TYVQHIKRRD

⁵³⁷

IVLKRELGEG

⁵⁴⁷

AFGKVFLAEC

⁵⁵⁷

YNLSPTKDKM

⁵⁶⁷

LVAVKALKDP

⁵⁷⁷

TLAARKDFQR

⁵⁸⁷

EAELLTNLQH

⁵⁹⁷

EHIVKFYGVC

⁶⁰⁷

GDGDPLIMVF

⁶¹⁷

EYMKHGDLNK

⁶²⁷

FLRAHGPDAG

⁶⁴⁹

ELGLSQMLHI

⁶⁵⁹

ASQIASGMVY

⁶⁶⁹

LASQHFVHRD

⁶⁷⁹

LATRNCLVGA

⁶⁸⁹

NLLVKIGDFG

⁶⁹⁹

MSRVYSTDYY

⁷¹⁰

RLHTMLPIRW

⁷³⁶

MPPESIMYRK

⁷⁴⁶

FTTESDVWSF

⁷⁵⁶

GVILWEIFTY

⁷⁶⁶

GKQPWFQLSN

⁷⁷⁶

TEVIECITQG

⁷⁸⁶

RVLERPRVCP

⁷⁹⁶

KEVYDVMLGC

⁸⁰⁶

WQREPQQRLN

⁸¹⁶

IKEIYKILHA

⁸²⁶

LGKATPIYLD

⁸³⁶

Click to Show 3D Structure of This Binding Site

set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .DZC or .DZC2 or .DZC3 or :3DZC;style chemicals stick;color identity;select .A:544 or .A:552 or .A:570 or .A:572 or .A:588 or .A:591 or .A:592 or .A:595 or .A:600 or .A:601 or .A:617 or .A:618 or .A:619 or .A:620 or .A:623 or .A:670 or .A:675 or .A:677 or .A:686 or .A:695 or .A:696 or .A:697 or .A:698; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all

Residue

Distance (Å)

LEU544

3.636

VAL552

3.793

ALA570

3.256

LYS572

3.589

GLU588

2.586

LEU591

3.554

LEU592

3.439

LEU595

3.627

ILE600

3.480

VAL601

3.647

PHE617

3.630

GLU618

3.187

Residue

Distance (Å)

TYR619

3.415

MET620

2.812

GLY623

3.961

LEU670

4.847

PHE675

3.732

HIS677

3.246

LEU686

3.480

ILE695

3.626

GLY696

3.204

ASP697

2.762

PHE698

3.237

Ligand Name: 4-[6-(Benzylamino)imidazo[1,2-B]pyridazin-3-Yl]benzonitrile

Ligand Info

Structure Description

(R)-2-Phenylpyrrolidine Substitute Imidazopyridazines: a New Class of Potent and Selective Pan-TRK Inhibitors

PDB:4YMJ

Method

X-ray diffraction

Resolution

2.00 Å

Mutation

[1]

PDB Sequence

GIHVQHIKRR

⁵³⁶

DIVLKRELGE

⁵⁴⁶

GAFGKVFLAE

⁵⁵⁶

CYNLSPTKDK

⁵⁶⁶

MLVAVKALKD

⁵⁷⁶

PTLAARKDFQ

⁵⁸⁶

REAELLTNLQ

⁵⁹⁶

HEHIVKFYGV

⁶⁰⁶

CGDGDPLIMV

⁶¹⁶

FEYMKHGDLN

⁶²⁶

KFLRAHGPGE

⁶⁵⁰

LGLSQMLHIA

⁶⁶⁰

SQIASGMVYL

⁶⁷⁰

ASQHFVHRDL

⁶⁸⁰

ATRNCLVGAN

⁶⁹⁰

LLVKIGDFGD

⁷⁰³

VYTDYYRHTM

⁷³¹

LPIRWMPPES

⁷⁴¹

IMYRKFTTES

⁷⁵¹

DVWSFGVILW

⁷⁶¹

EIFTYGKQPW

⁷⁷¹

FQLSNTEVIE

⁷⁸¹

CITQGRVLER

⁷⁹¹

PRVCPKEVYD

⁸⁰¹

VMLGCWQREP

⁸¹¹

QQRLNIKEIY

⁸²¹

KILHALGKAT

⁸³¹

Click to Show 3D Structure of This Binding Site

set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .4EJ or .4EJ2 or .4EJ3 or :34EJ;style chemicals stick;color identity;select .A:544 or .A:545 or .A:546 or .A:552 or .A:570 or .A:572 or .A:601 or .A:617 or .A:618 or .A:619 or .A:620 or .A:621 or .A:622 or .A:623 or .A:624 or .A:686 or .A:697 or .A:698 or .A:699; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all

Residue

Distance (Å)

LEU544

2.868

GLY545

2.383

GLU546

3.898

VAL552

3.211

ALA570

3.200

LYS572

3.230

VAL601

3.316

PHE617

2.562

GLU618

2.142

TYR619

2.995

Residue

Distance (Å)

MET620

2.192

LYS621

4.144

HIS622

4.801

GLY623

3.265

ASP624

3.833

LEU686

3.286

ASP697

4.925

PHE698

2.956

GLY699

4.149

Ligand Name: 1-(3-{[(3z)-2-Oxo-3-(1h-Pyrrol-2-Ylmethylidene)-2,3-Dihydro-1h-Indol-6-Yl]amino}phenyl)-3-[3-(Trifluoromethyl)phenyl]urea

Ligand Info

Structure Description

Discovery of a selective TRK Inhibitor with efficacy in rodent cancer tumor models

PDB:3V5Q

Method

X-ray diffraction

Resolution

2.20 Å

Mutation

[3]

PDB Sequence

GIHVQHIKRR

⁵³⁶

DIVLKRELKV

⁵⁵²

FLAECYNLSP

⁵⁶²

TKDKMLVAVK

⁵⁷²

ALPTLAARKD

⁵⁸⁴

FQREAELLTN

⁵⁹⁴

LQHEHIVKFY

⁶⁰⁴

GVCGDGDPLI

⁶¹⁴

MVFEYMKHGD

⁶²⁴

LNKFLRAHGP

⁶³⁴

ELGLSQMLHI

⁶⁵⁹

ASQIASGMVY

⁶⁶⁹

LASQHFVHRD

⁶⁷⁹

LATRNCLVGA

⁶⁸⁹

NLLVKIGDFG

⁶⁹⁹

MDVYSTDYYR

⁷¹¹

TMLPIRWMPP

⁷³⁹

ESIMYRKFTT

⁷⁴⁹

ESDVWSFGVI

⁷⁵⁹

LWEIFTYGKQ

⁷⁶⁹

PWFQLSNTEV

⁷⁷⁹

IECITQGRVL

⁷⁸⁹

ERPRVCPKEV

⁷⁹⁹

YDVMLGCWQR

⁸⁰⁹

EPQQRLNIKE

⁸¹⁹

IYKILHALGK

⁸²⁹

ATP

Click to Show 3D Structure of This Binding Site

set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .0F4 or .0F42 or .0F43 or :30F4;style chemicals stick;color identity;select .A:544 or .A:552 or .A:570 or .A:572 or .A:588 or .A:591 or .A:592 or .A:595 or .A:600 or .A:601 or .A:617 or .A:618 or .A:619 or .A:620 or .A:621 or .A:622 or .A:623 or .A:624 or .A:670 or .A:675 or .A:677 or .A:686 or .A:695 or .A:696 or .A:697 or .A:698; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all

Residue

Distance (Å)

LEU544

3.793

VAL552

4.254

ALA570

3.202

LYS572

3.472

GLU588

2.591

LEU591

3.530

LEU592

3.650

LEU595

3.706

ILE600

3.320

VAL601

4.212

PHE617

3.224

GLU618

2.812

TYR619

3.189

Residue

Distance (Å)

MET620

2.610

LYS621

3.704

HIS622

4.498

GLY623

3.459

ASP624

4.891

LEU670

3.680

PHE675

3.370

HIS677

3.232

LEU686

3.225

ILE695

3.152

GLY696

3.113

ASP697

2.605

PHE698

3.549

References

Top

REF 1

(R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors. ACS Med Chem Lett. 2015 Mar 16;6(5):562-7.

REF 2

Design, synthesis and biological evaluation of 3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-methylbenzamides as potent and selective pan-tropomyosin receptor kinase (TRK) inhibitors. Eur J Med Chem. 2019 Oct 1;179:470-482.

REF 3

Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models. ACS Med Chem Lett. 2012 Jan 1;3(2):140-5.

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