Possible new treatment targets in IBD

New treatment targets that have been tested preclinically or clinically are: highly selective small-molecule oral inhibitors of integrin α4β7, a CEACAM5 small peptide, the selective histone deacetylase (HDAC)6 inhibitor CKD-506, and a potent SIRT2-specific inhibitor, thiomyristoyl.

Integrins help facilitate immune cell trafficking and are an important receptor family for therapeutic intervention. The α4β7 integrin is an already clinically validated target for the treatment of inflammatory bowel disease (IBD): vedolizumab blocks the interactions between α4β7-expressing lymphocytes and its ligand mucosal addressin cell adhesion molecule-1 (MadCAM-1). In a study to develop and characterise orally bioavailable small-molecule inhibitors of the α4β7 integrin, a number of potent, selective, α4β7 integrin inhibitors were discovered that demonstrate on-target, mechanistic efficacy in 2 animal models of IBD [1]. The lead compound had favourable drug metabolism and pharmacokinetic properties, good oral bioavailability, and probably sufficient exposure in humans to effectively block α4β7-expressing immune cells. The authors therefore claimed this result could lead to an effective and safe monotherapy for IBD, which may also be combined with other IBD drugs.

Another study highlighted a new approach for modulating inflammation in Crohn’s disease (CD) by means of CEACAM5 small peptide [2]. Previously, a small region in CEACAM5 was identified that is able to restore the suppressive activity of CD8+ Treg cells in CD. In the new study, CEACAM5 small peptide activated CD8+ T cells from CD patients and significantly suppressed CD4+ T-cell proliferation [2]. The strongest suppression of proliferation was induced by a new small peptide from the overlapping peptide library containing N71. Peripheral CD8+ T cells increased IL-10 production upon stimulation with the CEACAM5 peptide.

CKD-506 is a selective inhibitor of HDAC6, a stress-inducible gene that is highly expressed in IBD. Molecular mechanisms of CKD-506 were identified [3]. CKD-506 was found to exert anti-inflammatory and anti-colitis effects through regulation of the NF-κB and AP-1 signalling pathway. Therefore, CKD-506 may provide beneficial effects in IBD patients.

Thiomyristoyl is a potent specific inhibitor of the HDAC SIRT2. Thiomyristoyl has shown extensive anticancer activity. A study of its anti-inflammatory properties revealed that thiomyristoyl ameliorates experimental colitis by blocking the differentiation of Th17 cells, which may be associated with the STAT3/IL-6 signal pathway [4]. The authors concluded SIRT2 may represent a potential target for IBD treatment.

1. 1. 1. Wong J, et al. ECCO-IBD 2020, DOP64.
      2. Roda G, et al. ECCO-IBD 2020, DOP66.
      3. Shin J, et al. ECCO-IBD 2020, DOP67.
      4. Xu Y, et al. ECCO-IBD 2020, DOP68.