Small molecule targeting of MIF as a novel melanoma therapeutic

点击翻译按钮获取中文摘要

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.