Macrophage migration inhibitory factor (MIF) is an upstream regulator of the immune response whose dysregulation is tied to a broad spectrum of inflammatory and proliferative disorders. As its complex signaling pathways and pleiotropic nature have been elucidated, it has become an attractive target for drug discovery. Remarkably, MIF is both a cytokine and an enzyme that functions as a keto-enol tautomerase. Strategies including in silico modeling, virtual screening, high-throughput screening, and screening of anti-inflammatory natural products have led to a large and diverse catalogue of MIF inhibitors as well as some understanding of the structure-activity relationships for compounds binding MIF's tautomerase active site. With possible clinical trials of some MIF inhibitors on the horizon, it is an opportune time to review the literature to seek trends, address inconsistencies, and identify promising new avenues of research.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is implicated in the regulation of inflammation, cell proliferation, and neurological disorders. MIF is also an enzyme that functions as a keto-enol tautomerase. Most potent MIF tautomerase inhibitors incorporate a phenol, which hydrogen bonds to Asn97 in the active site. Starting from a 113-μm docking hit, we report results of structure-based and computer-aided design that have provided substituted pyrazoles as phenol alternatives with potencies of 60-70 nm. Crystal structures of complexes of MIF with the pyrazoles highlight the contributions of hydrogen bonding with Lys32 and Asn97, and aryl-aryl interactions with Tyr36, Tyr95, and Phe113 to the binding.

The Front Cover reflects the optimization of inhibitors of the tautomerase activity of macrophage migration inhibitory factor (MIF) that feature a 4‐phenylpyrazole core. Starting from a weak docking hit (113 μM) at the bottom left of the gauge, structure‐based and computer‐aided design led to inhibitors of increasing potency, finally yielding the 67 nM biphenyl analog on the far right. Four crystal structures of complexes are reported, including the illustrated one for the 2‐naphthyl analog. Cover artwork by V. Trivedi‐Parmar and M. J. Robertson. More information can be found in the Communication by William L. Jorgensen et al. on page 1092 in Issue 11, 2018 (DOI: 10.1002/cmdc.201800158).