HTS to Identify Novel Chemical Probes for CCR6

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DESCRIPTION (provided by applicant): Chemokine receptors are members of one of the largest gene families encoded within the human genome; the class A, rhodopsin-like, G protein coupled receptors (GPCRs). These 7-transmembrane receptors and associated peptide ligands play a pivotal, yet complex role in directing leukocytic trafficking events in both homeostatic and disease states. We propose to initiate and develop a comprehensive high throughput screening assay platform to prosecute the CCR6/CCL20 receptor ligand pair. No small molecule receptor modulators have been reported in the literature to date. An important objective of this research program is to provide a tool to understand the functional significance of leukocyte trafficking modulated by the CCR6/CCL20 axis. 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. We show supporting preliminary data validating the role of CCR6 in B cell lymphoma and metastasis and provide a plan for an assay platform suitable for high throughput screening. Access to pharmacologically available small molecule antagonists will enable our further studies in disease relevant models. Specifically, we seek novel therapies for B cell lymphomas and subsequent arrest of metastasis. PUBLIC HEALTH RELEVANCE: Modulation and control of leukocyte cell trafficking in cancer provides a novel therapeutic mechanism for alleviation or cure of disease states. Our hypothesis is that regulation of the B cell chemokine receptor, CCR6, will be useful in preventing B cell based (lymphoma) tumor cell metastasis to the spleen and liver. Clinical biopsy samples should a marked up regulation of the CCR6 receptor on lymphoma B cells vs. normal activated ones. The ligand (CCL20) that attracts and controls the migration of these cells is present in the spleen and liver. Our preliminary study in mice, where the ligand is blocked by an antibody, demonstrates cell migration is stopped to a significant extent. No small molecule receptor modulators exist to date. The purpose of this project is to identify such a modulator through the high throughput screening of a small molecule collection with subsequent development of a preclinical small molecule probe to test our hypothesis.