Small molecule targeting of MIF as a novel melanoma therapeutic

描述（由申请人提供）：肿瘤相关巨噬细胞（tam）和髓源性抑制细胞（MDSCs）是实体瘤免疫抑制、新生血管形成和转移传播的重要决定因素。尽管人们已经努力确定TAM/MDSC调控效应物，但很少有人确定能够协调这一过程并有效靶向。巨噬细胞迁移抑制因子（Macrophage migration inhibitory factor， MIF）是已知最早的细胞因子之一，是单核细胞/巨噬细胞免疫应答的重要媒介。来自携带MIF缺陷的黑色素瘤小鼠的TAM和MDSCs在其“极化”状态中表现出独特的逆转，导致从免疫抑制、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），从而显著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) -在体外和体内都能充分概括MIF缺乏症，并有助于减轻TAM和MDSC的替代激活、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通过蛋白酶体依赖的方式显著降低细胞内MIF蛋白水平，从而在功能上抑制MIF。然而，相对较高的4-IPP IC50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表明，在将小分子靶向MIF推向临床之前，需要进行更多的研究来充分识别、优化和表征诱导MIF降解的先导化合物。为了实现此应用程序的既定目标，以下目标是

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.