T cell trafficking to the gut initiates mucosal inflammation in the intestine, a hallmark of Inflammatory Bowel Disease (IBD). Legacy and current agents for IBD have provided clinicians with effective treatment options comprised largely of biologics, including vedolizumab (Entyvio<sup>®</sup>), a monocolonal antibody targeting integrin α4β7. Orally available agents that can mitigate shortcomings in low colon perfusion, loss of response or extra-intestinal adverse events would provide attractive alternatives. Encycle Therapeutics employs proprietary cyclization chemistries to prepare nacellins, our brand of macrocycles, that exhibit drug-like properties including stability, amphipathicity and exposure. We conducted a discovery campaign starting from linear peptide ligands of integrin α4β7, focused on macrocyclization to optimize potency, selectivity against integrin α4β1 and DMPK. In pre-clinical mouse models of dextran sulfate sodium-induced colitis, nacellin antagonists of integrin α4β7 evoke prolonged receptor internalization in memory T cells in blood and exclusion of α4β7+ memory T helper cells from gut-associated lymphoid tissues. Several nacellins exhibit a balanced gut-plasma exposure profile and persistently suppress mechanisms of disease. Key features of the medicinal chemistry optimization will be presented.

Oral peptide macrocycle antagonists of integrin α4β7 for the treatment of IBD

256th National Meeting (2018)

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