HTS to Identify Novel Chemical Probes for CCR6

HTS 将鉴定 CCR6 的新型化学探针

• 批准号: 8134503
• 负责人: Gregory Paul Roth
• 金额: $ 4.78万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8134503
• 关键词: Address; Agonist; B-Cell Lymphomas; B-Lymphocytes; Binding; Biological Assay; Biopsy Specimen; Blocking Antibodies; CCL20 gene; CCR6 gene; Cells; Chemicals; Clinical; Collection; Complex; Data; Development; Disease; Dose; Event; G-Protein-Coupled Receptors; Gene Family; Hematopoietic Neoplasms; Human; Human Genome; Knowledge; Laboratories; Leukocyte Trafficking; Leukocytes; Libraries; Ligand Binding; Ligands; Literature; Liver; Lymphoma; Malignant Neoplasms; Methods; Modeling; Mus; Neoplasm Metastasis; Peptides; Physiological; Play; Publishing; Qualifying; Regulation; Reporting; Research; Rhodopsin; Role; Screening procedure; Sorting - Cell Movement; Spleen; Testing; Up-Regulation; Variant; base; biological research; cell growth regulation; cell motility; chemokine receptor; clinical application; expectation; high throughput screening; innovation; insight; member; novel; novel therapeutics; pre-clinical; prevent; programs; public health relevance; receptor; receptor function; response; small molecule; small molecule libraries; tool; trafficking

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.

描述（由申请人提供）：趋化因子受体是人类基因组内编码的最大基因家族之一的成员; A类视紫红质样G蛋白偶联受体（GPCR）。这些7-跨膜受体和相关的肽配体在体内平衡和疾病状态下指导白细胞运输事件中发挥关键而复杂的作用。我们建议启动和开发一个全面的高通量筛选分析平台，以起诉CCR 6/CCL 20受体配体对。迄今为止，文献中尚未报道小分子受体调节剂。这项研究计划的一个重要目标是提供一种工具，以了解由CCR 6/CCL 20轴调节的白细胞运输的功能意义。小分子工具将解决一个关键假设：CCR 6/CCL 20轴的调节将调节B细胞在包括造血系统恶性肿瘤和癌症转移在内的多种疾病中的致病活性。我们展示了验证CCR 6在B细胞淋巴瘤和转移中的作用的支持性初步数据，并提供了适合于高通量筛选的测定平台的计划。获得可获得的小分子拮抗剂将使我们能够在疾病相关模型中进行进一步的研究。具体而言，我们寻求新的治疗B细胞淋巴瘤和随后的转移停滞。 公共卫生关系：调节和控制癌症中的白细胞运输为缓解或治愈疾病状态提供了新的治疗机制。我们的假设是调节B细胞趋化因子受体CCR 6将有助于防止基于B细胞的（淋巴瘤）肿瘤细胞转移到脾和肝。临床活检样品应该是淋巴瘤B细胞上的CCR 6受体相对于正常活化细胞的显著上调。吸引和控制这些细胞迁移的配体（CCL 20）存在于脾脏和肝脏中。我们在小鼠中的初步研究，其中配体被抗体阻断，表明细胞迁移在很大程度上被阻止。迄今为止还不存在小分子受体调节剂。本项目的目的是通过高通量筛选小分子集合，随后开发临床前小分子探针来验证我们的假设，以确定这样的调节剂。