HTS to Identify Novel Chemical Probes for CCR6

描述(申请人提供)：趋化因子受体是人类基因组中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(GPCRs)。这些7-跨膜受体和相关的多肽配体在指导体内平衡和疾病状态下的白细胞转运事件中发挥着关键而复杂的作用。我们建议启动和开发一个全面的高通量筛选分析平台来进行CCR6/CCL20受体配体对的筛选。到目前为止，还没有小分子受体调节剂的文献报道。这个研究项目的一个重要目标是提供一个工具来理解CCR6/CCL20轴调节的白细胞运输的功能意义。一个小分子工具将解决一个关键假设：CCR6/CCL20轴的调节将调节B细胞在包括血液系统恶性肿瘤和癌症转移在内的各种疾病中的致病活动。我们提供了支持CCR6在B细胞淋巴瘤和转移中的作用的初步数据，并为适合高通量筛查的检测平台提供了计划。获得药理上可用的小分子拮抗剂将使我们在疾病相关模型中的进一步研究成为可能。具体地说，我们为B细胞淋巴瘤寻找新的治疗方法，并随后阻止转移。 公共卫生相关性：调节和控制癌症中白细胞的运输为缓解或治愈疾病状态提供了一种新的治疗机制。我们的假设是，调节B细胞趋化因子受体CCR6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脏。临床活检标本应与正常激活的淋巴瘤B细胞相比，显著上调淋巴瘤B细胞上CCR6受体的调节。吸引和控制这些细胞迁移的配体(CCL20)存在于脾和肝中。我们在小鼠身上的初步研究表明，在抗体阻断配体的情况下，细胞迁移在很大程度上被阻止。到目前为止还没有小分子受体调节剂存在。该项目的目的是通过高通量筛选小分子集合并随后开发临床前小分子探针来验证我们的假设，从而确定这样一个调节子。

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.