Metal-binding fragments vs GLO1

Practical Fragments has occasionally highlighted examples of metal-binding fragments. Strong interactions between low-molecular weight compounds and zinc, iron, or magnesium ions in metalloproteins makes for impressive ligand efficiencies. Unfortunately, some metal binders are PAINS and thus likely to inhibit a variety of targets; for others, the pharmacokinetic properties are not characterized. In a new J. Med. Chem. paper, Abraham Palmer, Seth Cohen, and colleagues at University of California San Diego describe a metallophilic molecule with in vivo efficacy.

The researchers were interested in glyoxalase 1 (GLO1), a zinc-dependent enzyme that catalyzes the clearance of the reactive metabolite methylglyoxal (MG). Although cytotoxic, MG may also have antidepressant effects. Thus, the researchers sought to find an inhibitor of GLO1.

They started by screening a library of 240 metallophilic fragments in a functional assay at 200 µM; more than 50 hits produced at least 50% inhibition. A second screen at 50 µM yielded 25 hits, including 8-MSQ.

Initial SAR studies revealed that both nitrogen atoms were essential for activity, suggesting a bidentate binding mode to the active-site zinc. Researchers at Chugai had previously reported a crystal structure of a very different molecule bound to GLO1, and this structure was used to model the binding mode of 8-MSQ. This exercise suggested growing from the sulfonamide, leading to compound 23. Incorporating information from other GLO1 inhibitors ultimately led to compound 60, with high nanomolar activity.

Those of you who have worked on drugs targeting the central nervous system may be concerned that compound 60 tends towards the large and lipophilic. However, when tested in mice at 12.5 mg/kg, it achieved a concentration of roughly 30 µM in the brain after two hours. Moreover, brain MG levels were increased 11-fold. Finally, mice dosed with compound 60 spent less time immobile in the forced swim test, a behavioral test used in rodent models of depression.

Overall, then, it seems that compound 60 has on-target activity in the brain and produces behavioral effects consistent with antidepressant activity. No selectivity data are provided, and because it could well be hitting other targets it is probably premature to use this as a chemical probe. Also, whether increasing the level of a toxic metabolite is a viable treatment for depression is likely to be hotly debated. Still, given the paucity of effective treatments for this widespread and devastating disease, it is nice to see researchers exploring bold mechanisms.