Macrophage Migration Inhibitory Factor (MIF) Enzymatic Activity and Lung Cancer

Leona Mawhinney, Michelle E. Armstrong, Ciaran O’Reilly, Richard Bucala, Lin Leng, Gunter Fingerle-Rowson, Darren Fayne, Michael P. Keane, Aisling Tynan, Lewena Maher, Gordon Cooke, David Lloyd, Helen Conroy, Seamas C. Donnelly

The cytokine macrophage migration inhibitory factor (MIF) possesses unique tautomerase enzymatic activity which contributes to MIF's biological functional activity. In this study, we investigated the effects of blocking the hydrophobic active site of MIF's tautomerase activity in the pathogenesis of lung cancer. To address this, we initially established a Lewis lung carcinoma (LLC) murine model in Mif-KO and wild-type (WT) mice and compared tumour growth in a knock-in mouse model expressing a mutant MIF lacking enzymatic activity (Mif(P1G)). Primary tumour growth was significantly attenuated in both Mif-KO and Mif(P1G) mice compared with WT mice. We subsequently undertook a structure-based, virtual screen to identify putative small molecular weight inhibitors specific for MIF's tautomerase enzymatic active site. From primary and secondary screens, the inhibitor, SCD-19 was identified which significantly attenuated MIF's tautomerase enzymatic activity in vitro and in biological functional screens. In the LLC murine model, SCD-19, given intraperitoneally at the time of tumour inoculation, was found to significantly reduce primary tumour volume by 90% (p<0.001) compared with the control treatment. To better replicate the human disease scenario, SCD-19 was given when the tumour was palpable (at day 7, post-tumour inoculation) and again, treatment was found to significantly reduce tumour volume by 81% (p<0.001) compared with the control treatment. In this paper, we identify a novel inhibitor which blocks the hydrophobic pocket of MIF, which houses it's specific tautomerase enzymatic activity, and demonstrate that targeting this unique active site significantly attenuates lung cancer growth in in vitro and in in vivo systems.