DOP64 Discovery of highly selective small-molecule oral inhibitors of integrin α4β7 for the treatment of inflammatory bowel diseases
J. WONG1, M. Bursavich2, N. Blanco1, A. Camblin1, L. Cappellucci1, R. Cohen1, D. Cui3, M. Krumpoch1, C. Zhong2, K. Hahn2, D. Lee3, B. Lippa2, F.Y. Lin4, A. Lugovsky5, M. McShea4, S. Mostafavi4, T. Moy1, A. Sullivan6, D. Troast2, L. Wang1, B. Rogers2
1Department of Biology, Morphic Therapeutic, Waltham, USA, 2Department of Chemistry, Morphic Therapeutic, Waltham, USA, 3Department of Drug Metabolism and Pharmacokinetics, Morphic Therapeutic, Waltham, USA, 4Department of Structural Biology, Morphic Therapeutic, Waltham, USA, 5Department of Development, Morphic Therapeutic, Waltham, USA, 6Department of Translational Sciences, Morphic Therapeutic, Waltham, USA
Integrins play a key role in facilitating immune cell trafficking throughout the body and represent an important receptor family for therapeutic intervention. In particular, the α4β7 integrin is a clinically validated target for the treatment of inflammatory bowel diseases (IBD), as exemplified by the humanised monoclonal antibody vedolizumab, which blocks the interactions between α4β7-expressing lymphocytes and its ligand MAdCAM-1. This blockade leads to the inhibition of these circulating lymphocytes from exiting the bloodstream and entering intestinal mucosal tissues resulting in a decrease in mucosal inflammation in patients. While oral inhibitors of the α4β7 integrin are advantageous over biologics, the efforts have been impeded by challenges to achieve desired selectivity and optimal DMPK properties. The aim of this study was to develop and characterise orally bioavailable small-molecule inhibitors of the α4β7 integrin and to determine their therapeutic potential.
Oral small-molecule inhibitors targeting the α4β7 integrin were discovered using Morphic Integrin Technology (MInT) platform. These small-molecule inhibitors were tested for potency and selectivity against a broad panel of integrin family members in multiple biochemical and cell-based functional assays in a ligand-competitive fashion. An acute PD assay with CFSE-labelled lymphocytes was developed to evaluate the activity of the small-molecule compounds in blocking lymphocyte trafficking to gut-associated lymphoid tissues in mice. The
Key drug candidate small molecules demonstrated over 1000-fold selectivity
Potent, selective, oral small-molecule inhibitors of α4β7 integrin have been discovered that demonstrate on-target, mechanistic efficacy in two animal models relevant to human IBD. It has the potential to be an effective and safe therapeutic in monotherapy as well as serving as a backbone for combination with other IBD drugs.