Targeting glutamate carboxypeptidase II in IBD

Over the past decade, the zinc metalloenzyme glutamate carboxypeptidase (GCPII) has emerged as a novel therapeutic target for IBD. This enzyme is minimally expressed in healthy ileum or colon, but is profoundly upregulated in multiple IBD subtypes including: adult and pediatric Crohn's disease (CD), adult and pediatric ulcerative colitis (UC), and UC pouchitis. Encouragingly, small molecule GCPII inhibitors display promising efficacy in chemical and genetic preclinical colitis models. In this chapter we will: (1) review GCPII biology, (2) present the data confirming its upregulation in IBD patients at gene and protein levels, (3) discuss foundational pre-clinical studies that established the anti-colitis efficacy of small molecule GCPII inhibitors, and (4) introduce the rationale and development of a novel class of GCPII inhibitors, including lead compound (S)-IBD3540, which hold therapeutic promise for IBD.