Drug discovery and chemokine receptor antagonists: eppur si muove!

Terricabras, Emma; Benjamim, Cláudia F.; Godessart, Núria

doi:10.1016/j.autrev.2004.07.037

Cited by 23 publications

(42 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Chemokine systems are different in mice and humans, although it is true that many murine chemokines will activate human CKRs and vice versa. Specific antagonists, however, may exhibit very different cross-species activity [107,128]. Extensive cross-species studies in vitro and a thorough understanding of structure-activity relationships are necessary before optimization of a compound suitable for any assay in vivo.…”

Section: The Discovery Of Ckr Antagonists By High Throughput Screeningmentioning

confidence: 99%

“…CKR antagonism has been validated in multiple clinical trials where several effective compounds have been advanced for asthma (CCR3, CXCR1/2), multiple sclerosis (CXCR3, CCR1, CCR5), rheumatoid arthritis (CCR1, CCR2, CCR5, CXCR2, CXCR3), chronic obstructive pulmonary disease (COPD) (CCR1, CXCR2), and HIV (CCR5 and CXCR4) [106,107] (Table 2).…”

Section: Approaches To the Development Of Thera-peutic Ckr Antagonistsmentioning

confidence: 99%

“…When CKRs are overexpressed in cell lines, they may be coupled with a different G protein than that found under native conditions [107]. Intracellular G proteins are effectors linking the receptor to a second messenger system such as adenylate cyclase, phospholipase and calcium ion channels.…”

Section: The Discovery Of Ckr Antagonists By High Throughput Screeningmentioning

confidence: 99%

“…A functional assay (assessment of a post-receptor events: calcium mobilization, cAMP stimulation, IP3 increase) for CKR activation (and inhibition) is preferred and can be automated for HTS [107] in 384-well plates. Such HTS have been improved with the use of fluorescent imaging plate reader (FLIPR)-calcium flux dye assays in which fewer false positives and less inter/intra plate variability are observed.…”

Section: The Discovery Of Ckr Antagonists By High Throughput Screeningmentioning

confidence: 99%

See 3 more Smart Citations

Chemokine Receptors as Targets for Cancer Therapy

Lee

Chevalier

et al. 2009

CPD

View full text Add to dashboard Cite

Chemokines and their receptors play critical roles in leukocyte trafficking during inflammatory processes. Although the role of chemokine receptors (CKRs) in cancer biology is a relatively new field of study, a growing body of data suggest that a number of CKRs, including CXCR4, CCR4, CCR7, and CCR10, may play diverse of roles in cancer growth, cancer metastasis, cancer angiogenesis, or the composition of the cancer microenvironment. Preclinical models of cancer indicate that cancer antagonists, most notably those for CXCR4, can block cancer growth either directly or by altering the cancer stroma. Highthroughput screening methods to identify effective CKR antagonists have been developed, but specificity, potency, and drug-delivery of validated candidate compounds remain issues that result in the clinical failure of many initially promising candidates. The recent approval of a CCR5 receptor antagonist in HIV suggests that safe, effective small molecular antagonists for other CKRs may not be far away. There is still a clear need to extend our understanding of the signalling pathways by which CKRs facilitate cancer processes. Because of the role of CKRs in cancer cell survival, the combination of CKR antagonists with traditional chemotoxic agents or with immunotherapy is an alluring strategy since this increases the specificity of treatment to the cancer and potentially limits additional systemic side effects.

show abstract

Section: The Discovery Of Ckr Antagonists By High Throughput Screeningmentioning

confidence: 99%

Section: Approaches To the Development Of Thera-peutic Ckr Antagonistsmentioning

confidence: 99%

Section: The Discovery Of Ckr Antagonists By High Throughput Screeningmentioning

confidence: 99%

Section: The Discovery Of Ckr Antagonists By High Throughput Screeningmentioning

confidence: 99%

See 2 more Smart Citations

Chemokine Receptors as Targets for Cancer Therapy

Lee

Chevalier

et al. 2009

CPD

View full text Add to dashboard Cite

show abstract

“…The use of different small molecules is proposed to be effective: small molecule chemokine receptor antagonists; chemokine-binding proteins, which could inhibit chemokine-chemokine receptor interactions; modified chemokines, which could interfere with normal chemokine function; and neutralizing antibodies, which may cause the blockade of chemokine receptors or the neutralization of particular chemokines (96). Various chemokine receptor antagonists have recently been discovered, and some of these are currently undergoing clinical trials in rheumatoid arthritis, psoriasis, HIV infection, and also MS (97)(98)(99). In EAE, CCR1 chemokine receptor knockout mice had a significantly lower incidence of disease and less CNS inflammation compared to wild-type mice.…”

Section: Chemokine System Intervention As a Potential Therapeutic Strmentioning

confidence: 99%

Chemokines and chemokine receptors in multiple sclerosis. Potential targets for new therapies

2007

View full text Add to dashboard Cite

Multiple sclerosis (MS) is a chronic demyelinating disease of the human central nervous system of a still unknown etiology. The autoimmune inflammatory process is believed to be essential for the development of the disease. Several different studies have shown that chemokines and chemokine receptors are involved in the pathogenesis of MS. Chemokines can mediate the trafficking of immune cells across the blood-brain barrier, and regulate their transfer to lesion sites. Chemokines were detected in actively demyelinating lesions and were found to be elevated in the cerebrospinal fluid of patients with MS during relapse. Different pairs of chemokine receptors and their ligands seem to play a pathogenic role in MS (e.g., CXCR3 and CXCL9, CXCL10; CCR1 and CCL3, CCL4, CCL5; CCR2 and CCL2; CCR5 and CCL3, CCL4, CCL5). Interfering with the chemokine system may be an effective therapeutic approach in MS. In this review we briefly summarize the results of the previous studies and identify the most important findings in the field.

show abstract

The Chemokine System and Arthritis

et al.

View full text Add to dashboard Cite

Rheumatoid arthritis (RA) affects 1% of the U.S. population, or 3 million people. RA is a chronic infl ammatory disease characterized by synovial infl ammation and hyperplasia, neovascularization, and progressive destruction of cartilage and bone. The cause(s) of RA remains poorly defi ned, but it is thought that both genetic and environmental factors, including molecular mimicry and host responses against cross-reactive antigens, lead to the development of autoimmune responses involving the joints. The goal of this chapter is to provide an overview of the contribution of members of the chemokine system to the immunopathogenesis of RA. This is of high clinical relevance because of the burgeoning interest in the use of chemokine and chemokine-receptor blockers in the treatment of a variety of infl ammatory, autoimmune, and infectious disorders, including RA.

show abstract

Drug discovery and chemokine receptor antagonists: eppur si muove!

Cited by 23 publications

References 26 publications

Chemokine Receptors as Targets for Cancer Therapy

Chemokine Receptors as Targets for Cancer Therapy

Chemokines and chemokine receptors in multiple sclerosis. Potential targets for new therapies

The Chemokine System and Arthritis

Contact Info

Product

Resources

About