Arginase-1 (Arg1) is the oldest known Mn2+-dependent human metalloenzyme. It is a homotrimeric enzyme, with each subunit bearing a dinuclear Mn2+ active site responsible for cleaving its substrate, L-arginine, to L-ornithine and urea. While the primary function of Arg1 is to complete the last step of the urea cycle in the liver, Arg1 is also distributed throughout the body where it plays various roles in maintaining homeostasis. Arg1 overexpression and subsequent L-arginine depletion have been linked to a number of diseases, including but not limited to cancer, hypertension, atherosclerosis, diabetic vascular disease, myocardial ischemia injury, ischemic stroke, Alzheimer’s disease, multiple sclerosis, diabetic retinopathy, and erectile dysfunction. Arg1 inhibition is proposed as a strategy for restoring L-arginine levels in these disease states, so that any new Arg1 inhibitor could be of great benefit to a range of conditions. Despite the known role of Arg1 overexpression in these diseases, there are currently no FDA approved therapeutics against this metalloenzyme. Reported inhibitor design has been sparse, and mainly limited to substrate analogues (oxidized guanidines) and transition state mimics (boronic acids). While these inhibitor classes have been useful as tool compounds, they have been found to have poor pharmacokinetic properties, stemming from limited bioavailability and in vivo stability, curtailing their potential for further therapeutic development. The ultimate goal of this research is to rationally design new, potent inhibitors of Arg1. In order to meet this goal, we have synthesized and screened our in-house metal-binding pharmacophore (MBP) library against Arg1 to identify MBP fragments that selectively bind to the dinuclear Mn2+ Arg1 active site. This screen has revealed multiple MBP small molecule scaffolds that selectively bind with sub 100 µM IC50 values against Arg1. These scaffolds include oxazoline and hydroxamic acid based inhibitors, both of which have never before been reported against Arg1. Moreover, rudimentary structure-activity relationship (SAR) derivatives of these MBP fragments has already yielded clear SAR trends identifying optimal positions for further compound elaboration. To this end, we are excited to report the development of new, metal-binding small molecule inhibitors of Arg1.

Metal-binding pharmacophores as scaffolds for the development of potent human arginase-1 inhibitors

2019 Fall National Meeting

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