Summary assay for selective small molecule antagonists of the CCR6 receptor
Currently there are no published patents or studies specifically describing small molecule antagonists of the chemokine receptor CCR6. CCL20 (MIP-3 alpha) is the endogenous peptide ligand for the G-protein coupled receptor (GPCR) CCR6. The receptor ligand pair is responsible for the chemoattraction of immature dendritic cells, effector/memory T cells, B cells, and also plays a role at skin and more ..
Data Source: Sanford-Burnham Center for Chemical Genomics (SBCCG)
Source Affiliation: Sanford-Burnham Medical Research Institute(SBMRI, San Diego, CA)
Network: NIH Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Number: R21 NS064746-01A
Assay Provider: Dr. Greg Roth, Sanford-Burnham Medical Research Institute
Currently there are no published patents or studies specifically describing small molecule antagonists of the chemokine receptor CCR6. CCL20 (MIP-3 alpha) is the endogenous peptide ligand for the G-protein coupled receptor (GPCR) CCR6. The receptor ligand pair is responsible for the chemoattraction of immature dendritic cells, effector/memory T cells, B cells, and also plays a role at skin and mucosal surfaces. The CCR6 receptor is expressed by B cells, subsets of T cells, and dendritic cells (DC). The link between the CCR6lCCL20 axis and cancer cell metastasis is a recent finding. There are two key studies that describe a relation between CCR6 and colorectal liver metastasis. The association between CCR6 expression levels in 64 primary tumor specimens in primary CRC and synchronous liver metastases suggests that CCR6 and CCL20 are involved in the metastatic spread to the liver. A small molecule tool would address a key hypothesis: Modulation of the CCR6/CCL20 axis will regulate pathogenic activities of B cells in a variety of diseases including hematopoietic malignancy and cancer metastasis.
The project goal is to identify a chemical probe of CCR6 receptor that can specifically act as 'chemical modulator' of CCR6 through inhibition (antagonism) of functional response and that is also selective against the human hCXCR5 and hCXCR4 receptors. The probe compound may function through either an orthosteric or allosteric mechanism. CXCR4 and CXCR5 are the counter receptors reported to be co-expressed in the relevant cell types and models for this project. An important objective of this research program is to provide new insight into the regulation of cancer metastasis modulated by the CCR6/CCL20 (MIP-3 alpha) axis.
This assay summarizes the screening activities for this project.
Schutyser, E.; Struyf, S.; Van Oamme, J. "The CC chemokine CCL20 and its receptor CCR6" Cytokine and Growth Factor Rev. 2003, 14,409-426.
Ghadjar P, Coupland SE, Na IK, Noutsias M, Letsch A, Stroux A, Bauer S, Buhr HJ, Thiel E, Scheibenbogen C, Keilholz U. "Chemokine receptor CCR6 expression level and liver metastasis In colorectal cancer" J. Clin. Oneal. 2006, 24, 1010-1016.
Rubie C, Oliveira V, Kempf K, Wagner M, Tilton B, Rau B, Kruse B, Konig J, Schilling M. "Involvement of chemokine receptor CCR6 in colorectal cancer metastasis" Tumour Biology 2006,27, 166-174.
Probe molecules are defined as the positives of this assay and assigned a score of 100. Testing has not progressed to the point where a probe molecule has been identified