ISO-66, a novel inhibitor of macrophage migration inhibitory factor, shows efficacy in melanoma and colon cancer models

Abstract

Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine, which possesses a contributing role in cancer progression and metastasis and, thus, is now considered a promising anticancer drug target. Many MIF-inactivating strategies have proven successful in delaying cancer growth. Here, we report on the synthesis of ISO-66, a novel, highly stable, small-molecule MIF inhibitor, an analog of ISO-1 with improved characteristics. The MIF:ISO-66 co-crystal structure demonstrated that ISO-66 ligates the tautomerase active site of MIF, which has previously been shown to play an important role in its biological functions. In vitro, ISO-66 enhanced specific and non-specific anticancer immune responses, whereas prolonged administration of ISO-66 in mice with established syngeneic melanoma or colon cancer was non-toxic and resulted in a significant decrease in tumor burden. Subsequent ex vivo analysis of mouse splenocytes revealed that the observed decrease in tumor growth rates was likely mediated by the selective in vivo expansion of antitumor-reactive effector cells induced by ISO-66. Compared to other MIF-inactivating strategies employed in vivo, the anticancer activity of ISO-66 is demonstrated to be of equal or better efficacy. Our findings suggest that targeting MIF, via highly specific and stable compounds, such as ISO-66, may be effective for cancer treatment and stimulation of anticancer immune responses.

MIF-Induced Stromal PKCβ/IL8 Is Essential in Human Acute Myeloid Leukemia

“…More recently, the ability of this cytokine to support tumor progression has been highlighted, revealing MIF as a potential target for anticancer therapies in melanoma and colon cancer (40). MIF occurs in immunologically distinct conformational isoforms, reduced MIF and oxidized MIF (oxMIF), with the latter predominantly expressed in patients with inflammatory diseases (41) and is highly expressed by various cancer cell lines (42).…”

Involvement of macrophage migration inhibitory factor in cancer and novel therapeutic targets

“…ISO-1 exerts an inhibitory action on cell migration and invasion in vitro in adenoid cystic carcinoma, as demonstrated by a decrease in MMP-9 expression (46). Additionally, an analog of ISO-1, ISO-66, has recently been reported to be active in melanoma and colon cancer models, where it decreases tumor growth by stimulating an antitumor immune response in vivo (56). Regarding head and neck carcinoma, our previous study investigated the effect of 4-IPP on SCCVII cells and reported that the pharmacological inhibition of MIF resulted in impaired proliferation and invasiveness in vitro (43).…”

A multi-targeted approach to suppress tumor-promoting inflammation

“…Anti-MIF therapeutics are therefore believed to have considerable promise for many types of cancer [53–57], Indeed several MIF-inactivating strategies have proven successful in delaying cancer growth, including ISO-66, a synthetic MIF inhibitor which caused a significant decrease in tumor burden when administered to mice with established syngeneic melanoma or colon cancer [58]. Recently human anti-MIF antibodies have been tested for their ability to influence growth rate and invasion of the human PC3 prostate cancer cell line in vitro , and in a PC3-xenograft mouse model in vivo .…”