Type

Journal Article

Authors

Seamas C Donnelly
Helen Conroy
David Lloyd
Gordon Cooke
Lewena Maher
Aisling Tynan
Michael P Keane
Darren Fayne
Gunter Fingerle-Rowson
Lin Leng
and 4 others

Subjects

Biochemistry

Topics
macrophage lung cancer mice factor tumor growth carcinoma lewis lung migration molecular weight

Macrophage Migration Inhibitory Factor (MIF) Enzymatic Activity and Lung Cancer. (2014)

Abstract The cytokine macrophage migration inhibitory factor (MIF) possesses unique tautomerase enzymatic activity, which contributes to the biological functional activity of MIF. In this study, we investigated the effects of blocking the hydrophobic active site of the tautomerase activity of MIF 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 tumor growth in a knock-in mouse model expressing a mutant MIF lacking enzymatic activity (Mif (P1G)). Primary tumor 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 the tautomerase enzymatic active site of MIF. From primary and secondary screens, the inhibitor SCD-19 was identified, which significantly attenuated the tautomerase enzymatic activity of MIF in vitro and in biological functional screens. In the LLC murine model, SCD-19, given intraperitoneally at the time of tumor inoculation, was found to significantly reduce primary tumor volume by 90% (p < 0.001) compared with the control treatment. To better replicate the human disease scenario, SCD-19 was given when the tumor was palpable (at d 7 after tumor inoculation) and, again, treatment was found to significantly reduce tumor volume by 81% (p < 0.001) compared with the control treatment. In this report, we identify a novel inhibitor that blocks the hydrophobic pocket of MIF, which houses its specific tautomerase enzymatic activity, and demonstrate that targeting this unique active site significantly attenuates lung cancer growth in in vitro and in vivo systems.
Collections Ireland -> Trinity College Dublin -> PubMed

Full list of authors on original publication

Seamas C Donnelly, Helen Conroy, David Lloyd, Gordon Cooke, Lewena Maher, Aisling Tynan, Michael P Keane, Darren Fayne, Gunter Fingerle-Rowson, Lin Leng and 4 others

Experts in our system

1
Seamas C Donnelly
TU Dublin (Tallaght Campus)
Total Publications: 35
 
2
David G Lloyd
Trinity College Dublin
Total Publications: 50
 
3
Gordon Cooke
TU Dublin (Tallaght Campus)
Total Publications: 20
 
4
Michael P Keane
University College Dublin
Total Publications: 23
 
5
Darren Fayne
Trinity College Dublin
Total Publications: 27