Small molecule targeting of MIF as a novel melanoma therapeutic

描述（由申请方提供）：肿瘤相关巨噬细胞（TAM）和髓源性抑制细胞（MDSC）是实体瘤免疫抑制、新生血管形成和转移性播散的重要决定因素。尽管密集的努力，旨在确定TAM/MDSC监管效应，很少有被确定为可以协调这一过程，并有效地针对。 巨噬细胞移动抑制因子（MIF）是一种最古老的细胞因子活性的描述和单核细胞/巨噬细胞免疫反应的中心重要介质。来自携带MIF缺陷型小鼠的黑素瘤的TAM和MDSC表现出其“极化”状态的独特逆转，导致从免疫抑制性血管生成表型（MIF+/+ TAM/MDSC）转变为免疫刺激性非血管生成表型（MIF-/- TAM/MDSC），这导致原发性和转移性黑素瘤疾病进展的显著减少。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）-在体外和体内均完全重现了MIF缺乏症，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功能性抑制MIF，显着降低细胞内的MIF蛋白水平，蛋白酶体依赖性的方式。然而，相对较高的4-IPP IC 50值以及缺乏关于其作用机制、生物利用度和慢性毒性的信息，决定了在临床环境中使用小分子MIF靶向之前，需要进行更多的研究来充分鉴定、优化和表征先导MIF降解诱导化合物。为了实现本申请的所述目的，以下目的是 提议：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：评价 主要MIF小分子拮抗剂作为个体和组合方式对已建立的黑色素瘤的治疗潜力。

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.