Arginase 1 (ARG1) is a trimeric binuclear metalloenzyme that hydrolyzes L-arginine in the urea cycle. T-cells require arginine for proliferation and activation. The extracellular space in the tumor micro-environment with high myeloid-derived suppressor cell (MDSC) infiltration is reported to be arginine-depleted and therefore unfavorable for a tumor-specific cytotoxic T-cell response. Consequently, ARG1 has become an emerging immuno-oncology target following literature reports that inhibition of this enzyme restores T-cell function by reversing MDSC suppression. Since the discovery of this enzyme and its potential role in oncology, the most potent ARG1 inhibitors reported are orthosteric binders and transition-state mimetics, e.g. boronic acid analogs of L-arginine such as (2)-S-amino-6-boronohexanoic acid (ABH). Although drugs containing boronic acids have been approved, it would be desirable to identify inhibitors lacking this motif. This work highlights our efforts to discover alternative non-boronic acid ARG1 inhibitors through virtual screening. We applied pharmacophore-based scaffold hopping and property-based filtering to identify novel chemotypes predicted to bind ARG1 with desirable physical properties. Pharmacophore models using known inhibitors were generated and queried against our internal compound database. To experimentally test the virtual screening hits, Rapid-Fire mass spectrometry was used to measure inhibition of ARG1 by directly monitoring the L-ornithine product produced by the enzyme. Further biochemical profiling and X-ray crystallography confirmed a class of non-boronic-acid pyrrolidine derivatives as low-micromolar ARG1 inhibitors. To the best of our knowledge, these ARG1 inhibitors are among the few non-boronic acid or non-transition-state analog identified to date. The binding mechanism, molecular interactions, and structure activity relationships (SAR) for this chemical class will be discussed in detail.

Discovery of non-boronic acid arginase 1 inhibitors through virtual screening

ACS Spring Meeting 2021

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