Merck UK - Calbiochem - Inhibitors: Phosphorylation/Dephosphorylation

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Technical Information

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Inhibitor Resource

Phosphorylation Dephosphorylation

Cyclin-dependent Kinase

DNA-Dependent Protein Kinase

Glycogen Synthase Kinase

c-Jun N-Terminal Kinase

IP3 Kinase & TGF-b Receptor I Kinase

Protein Tyrosine Kinase

Phosphorylation/Dephosphorylation: Protein Tyrosine Kinase (PTK) Inhibitors

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Inhibitors | Tyrphostins� | Non-Tyrphostin
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Protein tyrosine kinases (PTKs) play a key role in the regulation of cell proliferation, differentiation, metabolism, migration, and survival. PTKs catalyze the transfer of g-phosphoryl groups from ATP to tyrosine hydroxyls of proteins. They are classified as receptor PTKs and non-receptor PTKs. Receptor PTKs contain a single polypeptide chain with a transmembrane segment. The extracellular end of this segment contains a high affinity ligand-binding domain, while the cytoplasmic end comprises the catalytic core and the regulatory sequences. The cytosolic end also contains tyrosine residues, which become substrates or targets for the tyrosine kinase portion of the receptor. PTK remains inactive until a ligand binds to the receptor, which leads to the dimerization of two ligand-bound receptors (exception: the tetrametric insulin receptor). Once activated, receptors are able to autophosphorylate tyrosine residues outside the catalytic domain. This stabilizes the active receptor conformation and creates phosphotyrosine-docking sites for proteins that transduce signals within the cell. The cytosolic portion of the phosphorylated receptor recruits a number of cytosolic adapter proteins via interactions between phosphorylated tyrosine residues on the receptor and the SH2 domain on the adapter molecule. Different proteins have different SH2 domains that recognize specific phosphotyrosine residues. An SH2-containing protein, Grb2, acts as a common adapter protein in a majority of growth factor related signaling events.

Grb2 binding to phosphotyrosine residues changes its conformation and allows it to bind to proline-rich sequences in the carboxy terminal tail of Sos, a GDP-GTP exchange protein. This binding displaces an inhibitory domain in Sos and allows the activation of Sos, which then translocates to the plasma membrane to cause an exchange of GDP for GTP and activates Ras. A wide variety of effectors of Ras activation have been reported; however, activation of Raf, a cytoplasmic protein kinase, is one of the best studied examples. Ras binds to the N-terminus of

Raf and recruits it to the inner surface of the plasma membrane, where it is phosphorylated by protein kinase C. Translocation of Raf to the membrane positions it in direct proximity to MAP kinase kinase (MEK). Raf phosphorylates MEK, which in turn phosphorylates MAP kinase (MAPK). In a resting cell, MAPK remains inactive because its phosphorylation lip excludes ATP access to the binding pocket. However, MEK binding destabilizes the lip and exposes the buried tyrosine residues. Phosphorylation of the exposed tyrosine and the nearby threonine residues cause the lip to alter its conformation allowing ATP binding.

Non-receptor tyrosine kinases include members of the Src, Tec, JAK, Fes, Abl, FAK, Csk, and Syk families. They are located in the cytoplasm as well as in the nucleus. They are activated by a large number of stimuli including hormones, neurotransmitters, growth factors, and cytokines. They exhibit distinct kinase regulation, substrate phosphorylation, and function. Deregulation of these kinases has also been linked to several human diseases. In most cases, their activation also begins with the phosphorylation of a tyrosine residue present in an activation loop. The best studied enzymes in this group include Src kinases. Src is believed to be negatively regulated by phosphorylation at Tyr⁵²⁷ present at the C-terminus by Csk and other cellular kinases. The enzyme assumes an inactive conformation when this phosphotyrosine is bound by the Src SH2 domain in an intramolecular fashion. In this structure, the Src SH3 domain interacts with a single proline, Pro²⁵⁰, in the linker region between the SH2 and catalytic domain. In contrast to Src, c-Abl kinase activity is stimulated by phosphorylation of a catalytic domain tyrosine residue, Tyr⁴¹², either via autophosphorylation or transphosphorylation by c-Src. Recent studies have indicated that dimerization or oligomerization of c-Abl might also be sufficient to activate Abl kinase activity in vivo.

Due to their involvement in various forms of cancers, PTKs have become prominent targets for therapeutic intervention. Selective receptor and non-receptor PTK inhibitors represent a promising class of anti-tumor agents. These agents are shown to inhibit multiple features of cancer cells, including proliferation, survival, invasion, and angiogenesis.

Angiogenesis & Tumor
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Table 1: Tyrphostins: Inhibitory Effects on Protein Tyrosine Kinases

Product	Cat. No.	EGFR-K	Erb-2/Neu (HER-2)-K	PDGFR-K	p140^trk	IGF-1R-K	p60^c-src-K	Abl p210^bcr-abl
AG 9	658390	>1250^a	-	-	-	-	-	-
AG 10	658475	560^a
AG 17	658425	500^a		0.5	>100
AG 18	658395	40^a		25	>100	4000	440	75

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Table 2: Non-Tyrphostin Inhibitors of Protein Tyrosine Kinases

Product	Cat. No.	MW	Comments
Aminogenistein	155100	253.3	Inhibits protein-tyrosine kinase activity of p56^lck (IC₅₀ = 1.2 mM).
Angiogenesis Inhibitor	175580	211.2	A cell-permeable indolinone compound that displays anti-angiogenesis properties (30% inhibition of control at 10 mM in an in vitro rat aortic ring model ) with a potency that is comparable to that of SU5416 (Cat. No. 676487; 22% inhibition of control at 10 mM). Acts as a moderate ATP-competitive inhibitor of hEGF-R tyrosine kinase activity (54% inhibition at 10 mM).
BPDQ	203697	330.2	A highly potent and specific inhibitor of EGFR kinase (IC₅₀ = 120 pM).
BPIQ-I	203696	354.2	A highly potent and specific inhibitor of EGFR kinase (IC₅₀ = 25 pM). Also inhibits PLCg₁ at low concentrations (IC₅₀ = 8 pM).

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Inhibitors: Protein Tyrosine Kinase (PTK)

Product

Cat. No.

A77 1726

AG 9

AG 18

AG 43

AG 82

AG 99

AG 112

AG 183

AG 213

AG 490

AG 490, m-CF₃

AG 537

AG 555

AG 556

AG 825

AG 879

AG 957

AG 957, Adamantyl Ester

AG 1024

AG 1295

AG 1296

AG 1387

AG 1433

AG 1478

InSolution™ AG 1478

AG 17

AG 30

AG 527

AG 538

AGL 2043

AGL 2263

Aminogenistein

Angiogenesis Inhibitor

Bcr-abl Inhibitor

Bcr-abl Inhibitor II

BPDQ

BPIQ-I

BPIQ-II

Butein

CL-387,785

Compound 56

Cucurbitacin I, Cucumis sativus L.

238590

Curcumin, Curcuma longa L.

Daidzein

Damnacanthal

Daphnetin

5′-Deoxy-5′-methylthioadenosine

260585

17-DMAG

100069

DMBI

317200

EGF/FGF/PDGF Receptor Tyrosine Kinase Inhibitor NEW!

324841

EGFR Inhibitor

324674

EGFR Inhibitor II, BIBX1382

324832

EGFR/ErbB-2 Inhibitor

324673

EGFR/ErbB-2/ErbB-4 Inhibitor

324840

Emodin

324694

Erbstatin Analog

324930

FGF/VEGF Receptor Tyrosine Kinase Inhibitor, PD173074

341607

Flt-3 Inhibitor II

343021

Flt-3 Inhibitor III

343022

Flt3 Inhibitor IV NEW!

343023

cFMS Receptor Tyrosine Kinase Inhibitor

344036

Flt-3 Inhibitor

343020

cFMS Receptor Inhibitor III NEW!

344038

Geldanamycin, Streptomyces hygroscopicus

Genistein

Genistin

GTP-14564

Herbimycin A, Streptomyces sp.

HNMPA-(AM)₃

I-OMe-AG 538

IGF-1R Inhibitor II

IGF-1R Inhibitor, PPP

407247

Indirubin Derivative E804

402081

JAK Inhibitor I

420099

InSolution™ JAK Inhibitor I

JAK2 Inhibitor II

JAK3 Inhibitor I

JAK3 Inhibitor II

JAK3 Inhibitor III

JAK3 Inhibitor IV

JAK3 Inhibitor V

JAK3 Inhibitor VI

JAK3 Inhibitor, Negative Control

Lavendustin A

Lavendustin B

Lavendustin C

Lck Inhibitor

Lck Inhibitor II

Lck Inhibitor III

LFM-A11

LFM-A12

LFM-A13

Met Kinase Inhibitor

c-Met Kinase Inhibitor II

448102

Oxindole I

499600

PD 153035

234490

InSolution™ PD 153035

234491

PD 156273

513032

PD 158780

513035

InSolution™ PD 158780

513036

PD 168393

513033

PD 174265

513040

PDGFR Tyrosine Kinase Inhibitor I

521230

PDGFR Tyrosine Kinase Inhibitor II

521231

PDGFR Tyrosine Kinase Inhibitor III

521232

PDGFR Tyrosine Kinase Inhibitor IV

521233

PDGFR Tyrosine Kinase Inhibitor V

521234

Piceatannol

527948

PKC_bII/EGFR Inhibitor

539652

PP1 Analog

529579

PP1 Analog II, 1NM-PP1

PP2

InSolution™ PP2

PP3

Radicicol, Diheterospora chlamydosporia

553400

Src Kinase Inhibitor I

567805

Src Kinase Inhibitor II

567806

ST638

567790

Ste11 MAPKKK Activation Inhibitor NEW!

SU11652

SU1498

SU4984

SU5402

SU5614

SU6656

InSolution™ SU6656

Syk Inhibitor

Syk Inhibitor II

Syk Inhibitor III

Syk Inhibitor IV, BAY 61-3606

574714

(-)-Terreic Acid, Synthetic

581810

TGF-b RI Kinase Inhibitor II

616452

TGF-b RI Kinase Inhibitor

616451

TGF-b RI Kinase Inhibitor IV

2′-Thioadenosine

TrkA Inhibitor

TX-1123

TX-1918

Tyrene CR4

Tyrosine-Specific Protein Kinase Inhibitor

657015

VEGFR 2/3 Kinase Inhibitor

676499

VEGFR Tyrosine Kinase Inhibitor II

676481

VEGFR Tyrosine Kinase Inhibitor III, KRN633

676482

VEGFR Tyrosine Kinase Inhibitor IV

676483

VEGFR2 Kinase Inhibitor I

676480

VEGFR2 Kinase Inhibitor II

676485

VEGFR2 Kinase Inhibitor III

676487

VEGFR2 Kinase Inhibitor IV

676489

VEGFR2 Kinase Inhibitor VI, Ki8751

676484

InSolution™ VEGFR2 Kinase Inhibitor III

676498

VEGFR2/Flt3/c-Kit Inhibitor NEW!

676500

VEGFR3 Kinase Inhibitor, MAZ51

676492

Wee1 Inhibitor II

681641

Wee1/Chk1 Inhibitor

681637

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Other Related Products

Product

Cat. No.

Comments

Src Family Protein Tyrosine Kinase Inhibitor Set

567816

A set of 4 vials. Each set contains:

20 mg of Genistein (Cat. No. 345834)
100 mg of Herbimycin A, Streptomyces sp. (Cat. No. 375670)
1 mg of PP2 (Cat. No. 529573)
1 mg of PP3 (Cat. No. 529574).

Tyrosine Kinase Inhibitor Set II

657021

A set of 4 vials. Each set contains:

20 mg of Genistein (Cat. No. 345834)
1 mg of PP2 (Cat. No. 529573)
5 mg of AG 490 (Cat. No. 658401)
5 mg of AG 1296 (Cat. No. 658551)
5 mg of AG 1478 (Cat. No. 658552).

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Related Resources

PTK & Receptor Interactive Pathway

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