545.3 - A Novel Oral Glutamate Carboxypeptidase II Inhibitor for the Treatment of Inflammatory Bowel Disease
Monday, April 4, 2022
1:05 PM – 1:18 PM
Room: 109 AB - Pennsylvania Convention Center
Introduction: This session will highlight oral presentations by young scientists chosen from abstracts. Additionally, the session will feature talks from the division’s two Early Career Awardees.
Manisha Pradhan (Johns Hopkins University School of Medicine), Diane Peters (Johns Hopkins University School of Medicine), Lauren Norris (Johns Hopkins University School of Medicine), Ajit Thomas (Johns Hopkins University School of Medicine), Rana Rais (Johns Hopkins University School of Medicine), Barbara Slusher (Johns Hopkins University School of Medicine)
Presenting Author Johns Hopkins University School of Medicine
Inflammatory bowel disease (IBD) affects 1.3% of the US population, and approximately 40% of patients with moderate-to-severe disease are non-responsive to existing therapeutics. Glutamate carboxypeptidase II (GCPII), a membrane-bound zinc metallopeptidase, is highly upregulated in inflamed biopsies from patients with both Crohn’s disease and ulcerative colitis, as well as in preclinical colitis models. Previously, our lab and others have shown that small molecule GCPII inhibitors are efficacious in mouse colitis models when administered systemically or as enemas. To facilitate the clinical translation of this strategy, we have developed (S)-IBD3540, a gut-restricted and orally active small molecule GCPII inhibitor. (S)-IBD3540 is a potent GCPII inhibitor (IC50=4nM) with a desirable preclinical ADME and safety profile. We have characterized its anti-colitis activity in both acute and chronic mouse colitis models. When evaluated for efficacy in acute dextran sulfate sodium (DSS)-induced colitis, (S)-IBD3540 displayed: i) dose dependent inhibition of colon GCPII activity, ii) robust attenuation of colon inflammation, and iii) superior efficacy relative to clinical agents sulfasalazine and tofacitinib. We further confirmed (S)-IBD3540’s oral efficacy in spontaneous colitis of interleukin 10 knockout (IL10-/-) mice. Here, once daily oral treatment with (S)-IBD3540 in established colitis improved clinical signs and attenuated colon inflammation as measured longitudinally by ELISA for fecal LCN2, a non-invasive biomarker that correlates with intestinal inflammation. Overall, the GCPII inhibitor (S)-IBD3540 has an encouraging preclinical profile with robust efficacy in both acute (DSS) and chronic (IL10-/-) mouse models of colitis, and represents a promising new strategy for the treatment of IBD.
Support or Funding Information
This research supported by Crohns and Colitis Foundation IBD Ventures.
