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Small molecule enhancers of tumor immunity targeting the LPA5 GPCR

针对 LPA5 GPCR 的肿瘤免疫小分子增强剂

基本信息

批准号：
10535248
负责人：
CORINNE ELIZABETH AUGELLI-SZAFRAN
金额：
$ 86.18万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10535248
关键词：
Adoptive Transfer Allogenic Animals Antigens Antitumor Response Biological Assay Breast Breast Carcinoma C57BL/6 Mouse CD8-Positive T-Lymphocytes Cancer Patient Cellular Assay Cytotoxic T-Lymphocytes Data Development Disinhibition Docking Drug Kinetics Enhancers Enzymes G-Protein-Coupled Receptors Generations Genetic Goals Growth Human Immune system Immunologic Surveillance Immunomodulators Immunooncology Immunotherapy Impairment In Vitro Incidence Infiltration Interleukin-2 Knock-out Knockout Mice Lead Liver Lymphocyte Lymphocyte Function Lymphoma Lysophospholipase Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of ovary Measures Metastatic Neoplasm to the Lung Methods Modeling Molecular Mus Neoplasm Metastasis Outcomes Research Ovarian Pancreas Patients Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Physiological Preclinical Testing Process Production Property Publications Receptor Activation Receptor Signaling Research Research Personnel Resistance Role SUM-159 Breast Cancer Cell Line Solid Solubility Specificity Structure-Activity Relationship T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Toxic effect Transforming Growth Factor alpha Transgenic Mice Tumor Immunity Wild Type Mouse acute toxicity analog animal efficacy antagonist anti-tumor immune response antigen-specific T cells base beta-arrestin cancer cell cancer therapy cell killing clinical application cytotoxic cytotoxic CD8 T cells design drug discovery efficacy study high throughput screening human model immune checkpoint immune resistance immunological synapse formation in vivo indexing inhibitor iterative design lead candidate lead optimization lymphocyte proliferation lymphoid neoplasm lysophosphatidic acid macrophage melanoma mouse model neoplastic cell novel pharmacophore preclinical development receptor recruit refractory cancer response scaffold scale up secondary analysis small molecule small molecule inhibitor therapeutically effective tool tumor tumor microenvironment tumor progression virtual virtual screening

项目摘要

Lysophosphatidic acid (LPA) GPCR subtype 5 (LPAR5) is abundantly expressed by human and murine CD8 cytotoxic T lymphocytes (CTLs) and functions as an inhibitory receptor that represses T cell receptor (TCR) signaling leading to inhibition of tumor immunity. Specifically, stimulation of LPAR5 by physiological levels of LPA significantly impedes antigen specific TCR-induced Ca2+ mobilization, T cell activation, proliferation and cytolytic tumor cell killing functions, resulting in an impaired anti-tumor immune response. Indeed, CD8+ T cells lacking LPAR5 expression are more effective at reducing the growth rate of EG7 lymphoma and B16 melanoma tumors in mice compared to wild type (WT) CD8+ T cells. Moreover, Lpar5 -/- mice have 85% reduction in the incidence of B16 melanoma-derived lung metastasis compared to WT littermates, with a robust CD8+ CTL infiltration observed in the Lpar5 -/- mice that developed few lung metastasis. These data highlight a unique role for LPAR5 as an immune checkpoint molecule regulating immune surveillance and cytotoxic effector function. The objective of this proposal is to identify small molecule inhibitors of LPAR5 as clinically applicable immunomodulators for cancer treatment. A virtual screening (VS) of 2 million compounds using validated LPAR models identified more than 300 hits of which 90 were selective for LPAR5 antagonist compounds with diverse scaffolds. In addition, a high throughput screening (HTS) campaign of 200K compounds and secondary analyses of 19 validated hits have already resulted in the identification of two distinct molecular scaffolds. The most promising hit, SRI-42730, demonstrated LPAR5 antagonism in five independent assays: β-arrestin recruitment, Ca2+ mobilization, TGFα-shedding, IL-2 production implemented in HTS platform and in vivo efficacy in the B16 murine melanoma metastasis model. The novel hits and analogs we have already identified will be used as tool compounds in the following proposed studies: 1) Perform hit-to-lead medicinal chemistry optimization of LPAR5 antagonists. Computational approaches will include scaffold hopping on HTS hits, and the generation of a pharmacophore model to aid synthetic optimization of potency and selectivity of newly designed analogs; 2) Determine the specificity of novel antagonists at LPA GPCR subtypes and autotaxin lysophospholipase enzyme; 3) Rank specific antagonist hits by potency in boosting antigen-specific TCR activation and IL-2 production in the presence of LPA; 4). 8 key compounds will then be evaluated in cellular assays from which 3 compounds will undergo PK analysis prior to in vivo tox studies and animal efficacy studies. 5) Determine efficacy of nominated three potential lead compounds in boosting tumor immunity using murine and allogeneic human in vitro tumor killing assays and in vivo murine metastasis seeding and progression models. The impact of this research will be the identification and nomination of a single lead compound and a pool of structurally diverse LPAR5 antagonists for further preclinical development.

溶血磷脂酸（LPA） GPCR亚型5 （LPAR5）在人和小鼠CD8中大量表达