cell migration inhibitors

8/10/2019 Cell Migration Inhibitors

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Introduction

Immune cells are recruited to sites of inflammation

through

– binding to adhesion molecules on vascular endothelial cells

– and by chemoattractants produced locally.

A potential strategy to treat and prevent inflammatorydiseases is to inhibit the processes of adhesion,

migration, and recruitment of leukocytes.



Adhesion and Recruitment of Inflammatory Cells

Multistep process involving

– adherence of circulating leukocytes to endothelial

cells on post - capillary venules

– migration through the vessel wall.

Each step is orchestrated by several different types of

molecules, all of which provide potential targets for

inhibition of this process



Leukocyte adhesion cascade

Leukocyte extravasation usually occurs through a multistep process,

involving first the selectins, then chemoattractant receptor signaling,

followed by firm adhesion to vessel walls through the actions of integrins



Selectins

CD62 family of cell adhesion molecules

TNF, IFN - γ and IL - 1 are major inducers of selectin expression.

Endothelial cells express P- selectin and E - selectin.

Leukocytes express a third selectin,

– L-selectin (CD62L),

– carbohydrate ligands for P - and E - selectins on their

surface, facilitating interactions with endothelial surface

molecules

These are low affinity interactions.



Chemokines

Small polypeptide molecules produced by numerous celltypes in the inflammatory microenvironment.

Chemokines stimulate chemotaxis of cells toward a

concentration gradient of these proteins.

The CC chemokines are distinguished by adjacent

cysteines and attract monocytes and T cells.

The CXC chemokines have motifs with two cysteines

separated by another amino acid and attract neutrophils,

dendritic cells and naïve T cells.



Chemokines

Chemokines bind to specific chemokine receptors on the

surface of rolling leukocytes.

Chemokine receptor signaling results in enhanced affinity of

leukocyte integrins for their endothelial ligands.

The number of chemokines and other chemoattractants

suggest that these latter molecules must be prominent in

dictating the precise placement of leukocyte subsets.



Integrins

Plays role in stable adhesion of leukocytes to the

endothelium occurs.

Heterodimeric cell surface proteins composed of two non-

covalently linked polypeptide chains, α and β , expressed

on the surface of leukocytes .

Leukocyte integrin binding to endothelial ligands mediates

cell type - and organ - specific cell recruitment to sites of

inflammation.



Integrins

For example, the α4β1 integrin heterodimer recognizes the

vascular cell adhesion molecule- 1 (VCAM- 1).

Inflammatory cytokines such as TNF and IL- 1 also enhance

endothelial expression of integrin ligands, such as VCAM - 1 and

intercellular adhesion molecule- 1 (ICAM - 1; the ligand for αLβ 2

integrin or LFA - 1).

When α4 pairs with the integrin molecule β7, this is an intestine -

specific signal through recognition of its endothelial ligand

MadCAM- 1.



Integrins

Tissue specific and inflammatory zip codes” directing

leukocytes to a specific endothelial “mailbox” to initiate

the next step of transmigration.

When these interactions occur, leukocytes attach firmly

to the endothelium.



Leukocyte transmigration

In the final step, leukocytes transmigrate through the endothelium.

Chemokines play an important role by directing cells to migrate

through inter - endothelial spaces along a chemical concentration

gradient.

Combinations of adhesion molecules and chemokine receptors on

distinct leukocyte populations, and expression of respective ligands on

endothelial cells result in cell type- and tissue - specific leukocyte

recruitment.

understanding specificity behind these processes has led to the

development of therapies that inhibit recruitment of inflammatory

cells in an organ - specific manner.



Points where cell migration molecules operate

during inflammatory responses



Cell migration inhibitors

Four classes.

Three of these represent the three types of molecules

involved in cell migration and adhesion:

I. the selectins and their receptors,

II. the chemoattractants and their receptors, and

III. the integrins and their receptors.

A fourth class includes

IV. the signaling molecules downstream from adhesion or

chemoattractant receptors, such as phosphoinositide-3-OH

kinase-γ (PI(3)K- γ ).



Selectin inhibitors

P-selectin glycoprotein ligand-1 (PSGL-1) - mucin-like

glyco-protein that binds P- , L- and E-selectin.

It is expressed on certain leukocytes, as well as inflamed

endothelial cells.

Cutaneous lymphocyte-associated antigen (CLA)

represents a modified form of PSGL-1 that interacts with

E-selectin for skin homing by T cells.

Blockade of selectins or PSGL-1 inhibits several

inflammatory conditions, at least in animal models



Integrin inhibitors

Natalizumab

the mAb to α4 integrin developed by Biogen-Idec and Elan for the treatment of

multiple sclerosis and Crohn’s disease.

Several studies in rodents indicated that an α4integrin inhibitor should be highly

effective for human multiple sclerosis and inflammatory bowel disease.

The results of two phase 3 clinical trials showed that natalizumab markedly reduces

the number of relapses in individuals with multiple sclerosis.

The notable adverse effect of these trials was the development in two subjects of

progressive multifocal leukoencephalopathy, a condition caused by a polyoma virus, JC

virus.

This complication has resulted in restrictions on the type of patient that can receive

the drug.



Integrin inhibitors

Efaluzimab

Humanized mAb that was approved in 2003 Targetting LFA-1 (CD11a)

For the treatment of moderate to severe plaque psoriasis.

A recently published long-term study demonstrated sustained improvement

in psoriasis symptoms in subjects throughout three years of continuous

Treatment

Thus, efaluzimab is one of the most effective treatments for psoriasis at

present.

The successful molecular modeling of integrins has allowed development

of small molecule allosteric antagonists and ligand mimetics.



Chemoattractant receptor inhibitors

C5a receptors one of the most potent chemoattractants for neutrophils and

eosinophils. It also activates other leukocytes including mast cells

and basophils.

overproduced C5a or upregulated C5aR expression has been

implicated in the pathogenesis of rheumatoid arthritis, respiratory

distress syndrome, inflammatory bowel disease, systemic lupus

erythematosus (SLE), ischemia-reperfusion injury, COPD and sepsis.

Novo Nordisk and G2 Therapies have developed a high-affinity mAb

to human C5aR (ref. 19), which is now in early clinical trials.



CXCR2 and CXCR1

A number of CXCR2 –CXCR1 antagonists are in human

clinical trials.

SCH 527123

The most advanced being Schering-Plough’s CXCR2

small molecule inhibitor already in phase 2 trials forCOPD and ‘neutrophilic’ asthma.




CCR2 antagonists

INCB3284 by Incyte

which is now in phase 2a clinical trials in patients with

rheumatoid arthritis and type 2 diabetes.

MK0812 by Merck

in phase 2 trials in subjects with multiple sclerosis.




tissue-specific cell migration inhibitors

CCX282 (Traficet-EN)

CCR9 inhibitor from ChemoCentryx.

CCR9+ T cells contribute to pathogenesis of inflammatory

bowel disease.

Now in late stage clinical trials.



Blockade of lymphocyte egress

FTY-720 (Fingolimod)

S1P receptor agonist

FTY-720 causes lymphocyte retention in lymph nodes, with a consequent

lymphopenia in blood.

S1P

the “exit signal” for lymphocytes leaving lymphoid organs and

is present in blood and lymph at high concentrations due to the S1P

producing activity of sphingosine kinases.

Conversely, the S1P degrading enzyme, S1P lyase, maintains low amounts

of S1P in lymphoid organs.



FTY-720 (Fingolimod)

Disrupting this concentration gradient by S1P receptor agonists, anti- S1P

antibodies or S1P lyase inhibitors have therapeutic potential for

autoimmune diseases like MS and rheumatoid arthritis.

FTY-720 sequesters lymphocytes in secondary lymphoid organs,

thereby preventing their migration to sites of inflammation.

This drug showed promising phase 2 clinical trial results in MS.

One potential side-effect of FTY-720 treatment is bradycardia due to

expression of certain S1P receptors, particularly S1P3, in the heart.

Hence, development of agonists that are

selective for one particular receptor subtype, S1P1, are being pursued

vigorously by several pharmaceutical companies.



The signaling molecules downstream from

adhesion or chemoattractant receptors

The most promising class of such signaling molecules is PI(3)Ks

Mice lacking one of the four isoforms, PI(3)K γ , possess neutrophils

and macrophages that show impaired activation through

chemoattractant receptors and poor chemotac-tic responses.

These mice are also protected in various models of inflammation,

including inflammatory arthritis and glomerulo -nephritis

Several drug companies have produced effective small

molecule inhibitors of PI3K γ



Promising targets and drug development programs for cell

migration inhibitor

cell migration inhibitors

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