Small molecule targeting of MIF as a novel melanoma therapeutic

MIF 小分子靶向作为新型黑色素瘤治疗药物

基本信息

批准号：
8720982
负责人：
ROBERT A MITCHELL
金额：
$ 31.13万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-03 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8720982
关键词：
5&apos -AMP-activated protein kinase American Antibody Therapy Attenuated Binding Biological Availability Cancer Center Cancer Patient Cells Chemotherapy-Oncologic Procedure Chimeric Proteins Chronic Clinical Clinical Trials Denileukin Diftitox Diagnosis Disease Progression Drug Targeting Effector Cell Exhibits Future Gene Expression Goals Growth IL2 gene IL2RA gene Immigration Immune Immune response Immunosuppression Immunosuppressive Agents Immunotherapeutic agent Immunotherapy In Vitro In complete remission Individual Inhibitory Concentration 50 Invaded Lead Lesion Ligands Lung Malignant Neoplasms Mediator of activation protein Metastatic Melanoma Migration Inhibitory Factor Modality Molecular Profiling Mus Myelogenous Neoplasm Metastasis Outcome Pathway interactions Patients Phenotype Population Process Proteins Quantitative Structure-Activity Relationship Regulatory T-Lymphocyte Resistance Role Signal Pathway Skin Cancer Solid Solid Neoplasm Specificity Staging Suppressor-Effector T-Lymphocytes Survival Rate Testing Therapeutic Toxic effect Tumor-Derived United States analog angiogenesis base cancer cell cell motility clinical efficacy combinatorial cytokine design improved in vivo inhibitor/antagonist insight lifetime risk macrophage melanoma monocyte mouse model multicatalytic endopeptidase complex neovascularization novel novel therapeutics partial response phenylpyruvate tautomerase prevent public health relevance receptor scaffold small molecule subcutaneous therapeutic target tumor tumor microenvironment tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are critically important determinants of solid tumor immunosuppression, neovascularization and metastatic dissemination. Despite intensive efforts aimed at identifying TAM/MDSC regulatory effectors, very few have been identified that can orchestrate this process and be effectively targeted. Macrophage migration inhibitory factor (MIF) is one the oldest cytokine activities described and is a centrally important mediator of monocyte/macrophage immune responses. TAMs and MDSCs from melanoma bearing MIF-deficient mice exhibit a unique reversion in their "polarization" state resulting in a switch from n immunosuppressive, angiogenic phenotype (MIF+/+ TAM/MDSC) into an immunostimulatory, non-angiogenic phenotype (MIF-/- TAM/MDSC) which results in significant reductions in primary and metastatic melanoma disease progression. Intriguingly, our previously discovered MIF small molecule antagonist - 4-iodo-6- phenylpyrimidine (4-IPP) - fully recapitulates MIF-deficiency, both in vitro and in vivo, and serves to attenuate TAM and MDSC alternative activation, immunosuppression, neoangiogenesis and melanoma disease progression [1601]. We very recently discovered that 4-IPP functionally inhibits MIF by dramatically reducing intracellular MIF protein levels in a proteasome-dependent manner. However, relatively high 4-IPP IC50 values and a lack of information on its mechanism of action, bioavailability and chronic toxicity dictate that much more study is needed to fully identify, optimize and characterize lead MIF-degradation inducing compounds before moving forward with small molecule MIF targeting in a clinical setting. To fulfill the stated objectives of this application, the following aims are proposed: Aim 1: Delineate the mechanisms of action of 4-IPP and MIF-dependent TAM/MDSC polarization, Aim 2: Characterize TAM/MDSC modulatory, in vivo bioavailability, toxicity and anti-tumor activities of existing and newly identified MIF inhibitor scaffolds, and Aim 3: Evaluate the therapeutic potential of lead MIF small molecule antagonists as individual and combinatorial modalities against established melanoma.

描述（由申请人提供）：肿瘤相关巨噬细胞（TAM）和骨髓源性抑制细胞（MDSC）是实体瘤免疫抑制、新血管形成和转移扩散的极其重要的决定因素。尽管为识别 TAM/MDSC 调节效应器付出了巨大的努力，但很少有人能够协调这一过程并有效地瞄准目标。巨噬细胞迁移抑制因子（MIF）是描述的最古老的细胞因子活性之一，并且是单核细胞/巨噬细胞免疫反应的核心重要介质。来自带有 MIF 缺陷的黑色素瘤小鼠的 TAM 和 MDSC 在其“极化”状态中表现出独特的逆转，导致从 n 免疫抑制、血管生成表型 (MIF+/+ TAM/MDSC) 转变为免疫刺激、非血管生成表型 (MIF-/ - TAM/MDSC），可显着减少原发性和转移性黑色素瘤疾病的进展。有趣的是，我们之前发现的 MIF 小分子拮抗剂 - 4-碘-6-苯基嘧啶 (4-IPP) - 在体外和体内完全重现了 MIF 缺陷，并用于减弱 TAM 和 MDSC 替代激活、免疫抑制、新血管生成和黑色素瘤疾病进展[1601]。我们最近发现 4-IPP 通过以蛋白酶体依赖性方式显着降低细胞内 MIF 蛋白水平来功能性抑制 MIF。然而，相对较高的 4-IPP IC50 值以及缺乏有关其作用机制、生物利用度和慢性毒性的信息表明，在继续使用小分子之前，需要进行更多的研究来充分识别、优化和表征先导 MIF 降解诱导化合物临床环境中的 MIF 靶向。为了实现本应用程序的既定目标，以下目标是提出：目标 1：描述 4-IPP 和 MIF 依赖性 TAM/MDSC 极化的作用机制，目标 2：表征现有和新鉴定的 MIF 抑制剂支架的 TAM/MDSC 调节、体内生物利用度、毒性和抗肿瘤活性，以及目标 3：评估先导 MIF 小分子拮抗剂作为单独和组合疗法对抗已确定的黑色素瘤的治疗潜力。