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Diane Peters, Lauren Norris, Lukas Tenora, Ivan Snajdr, Xiaolei Zhu, Shinji Sakamoto, Ajit Thomas, Pavel Majer, Rana Rais, Barbara Slusher, DISCOVERY OF IBD3540: A NOVEL GUT-RESTRICTED GLUTAMATE CARBOXYPEPTIDASE II INHIBITOR WITH ORAL ACTIVITY IN MOUSE COLITIS MODELS, Inflammatory Bowel Diseases, Volume 28, Issue Supplement_1, February 2022, Page S4, https://doi.org/10.1093/ibd/izac015.007
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Abstract
Glutamate carboxypeptidase II (GCPII) is robustly overexpressed in both Crohn’s disease and ulcerative colitis and is a promising therapeutic target for IBD. We have previously published that systemically or enema administered small molecule GCPII inhibitors have efficacy in multiple mouse colitis models. While this is a highly encouraging activity profile for a candidate IBD drug, an oral dose route would be strongly preferred. Thus, here we develop and characterize a new class of GCPII inhibitors designed to be gut-restricted for oral administration, with the intention of selecting a lead inhibitor for further clinical development.
Anti-inflammatory secondary bile acids lithocholic acid, deoxycholic acid and ursodeoxycholic acid were conjugated to GCPII inhibitor, 2-PMPA, yielding three novel constructs. These conjugates were screened for oral activity in murine dextran sulfate sodium (DSS) colitis, followed by detailed characterization of the most active inhibitor to: measure GCPII inhibition (IC50), confirm colon target engagement, evaluate plasma and colon pharmacokinetic profiles, compare efficacy versus standard-of-care agents, evaluate mechanisms of anti-inflammatory activity in vivo, confirm efficacy in a second colitis model (IL10-/-), and assess safety in standard preclinical assays.
The deoxycholic acid 2-PMPA conjugate, IBD3540, was identified as the lead inhibitor (IC50 = 4nM). Oral IBD3540 was robustly efficacious in acute DSS colitis, where it dose-dependently inhibited colon GCPII, attenuated both gross disease activity index and blinded colon histopathology scores, and exhibited improved efficacy relative to both sulfasalazine and tofacitinib when compared head-to-head. Mechanistically, we determined that IBD3540 attenuated pathogenic monocytic inflammation in the colon, as measured by flow cytometry, and also decreased colon pro-inflammatory cytokine content. We confirmed efficacy of IBD3540 in spontaneously occurring, chronic, IL10-/- colitis, where treatment initiated 4 weeks after the onset of colon inflammation improved multiple disease endpoints. Further, in preclinical safety screens, inclusive of CYP inhibition/induction assays, Eurofins SafetyScreen44, and AMES/hERG mutagenicity testing, no concerns were identified.
IBD3540 is a novel, gut-restricted, GCPII inhibitor with potent oral anti-colitis efficacy in both acute (DSS) and chronic (IL10-/-) mouse colitis models and a promising preclinical safety profile. Further development of this mechanistically unique candidate IBD drug is warranted.
- anti-inflammatory agents
- cytokine
- herg
- inflammation
- bile acids
- crohn's disease
- inflammatory bowel disease
- ulcerative colitis
- enema solution
- flow cytometry
- administration, oral
- colitis
- deoxycholic acid
- dextran sulfate
- drug administration routes
- interleukin-10
- lithocholic acid
- monocytes
- mutagenicity tests
- plasma
- safety
- sulfasalazine
- ursodiol
- colon
- enema administration
- mice
- sodium
- tenofovir
- glutamate carboxypeptidase ii
- standard of care
- surrogate endpoints
- small molecule
- attenuation
- tofacitinib
- histopathology tests