P120 BBT-401 IS A SELECTIVE PELLINO-1 PROTEIN-PROTEIN INTERACTION INHIBITOR IN CLINICAL DEVELOPMENT TARGETING A FIRST-IN-CLASS DRUG FOR UC TREATMENT. (7th February 2019)

• Record Type: Journal Article
• Authors: Lee, Gwanghee; Lee, YounSook; Chang, Mikyoung; Kang, Sang U K; Ryou, Jeong-Hyun; Lim, Jong-Jin; Imran, Ali; Park, Seok-Hee; Lee, Kwangho; Lee, Yong-Hee
• Is Part Of: Inflammatory bowel diseases. Volume 25(2019)Supplement 1
• Page Start: S58
• Page End: S58
• Publication Date: 2019-02-07
• Subjects: Inflammatory bowel diseases -- Periodicals; Colitis, Ulcerative -- Periodicals; Crohn Disease -- Periodicals; Inflammatory Bowel Diseases -- Periodicals; 616.344
• DOI: 10.1093/ibd/izy393.131
• Languages: English
• ISSNs: 1078-0998

Abstract

Abstract: Toll-like receptor (TLR) pathways play a pivotal role during the pathogenesis of inflammatory diseases including ulcerative colitis (UC) by recognizing pathogen-associated molecular patterns and consequently inducing proinflammatory signals. Pellino-1 is an E3 ubiquitin ligase and contributes to the innate immune response through the interaction with key signaling molecules including MyD88 and RIP kinases upon the receptor engagement. Mice deficient for Pellino-1 were viable and healthy, but completely protected from a septic shock when challenged with the lethal dose of lipopolysaccharide (LPS). The inflammatory cytokine level was dramatically decreased in the serum of the Pellino-1 (-/-) mice and in mouse embryonic fibroblasts generated from the mice, which demonstrate the critical role played by Pellino-1 during the inflammatory response. BBT-401, Pellino-1 protein-protein interaction inhibitor, is in clinical development to treat UC patients. BBT-401 is an orally available lipidated tetra-peptide, specifically binds to Pellino-1 and dissociates the multi-protein signaling complexes containing MyD88 and RIP1 kinase, respectively. The BBT-401 treatment efficiently inhibited the LPS-induced activation of the TLR-NFkB signaling pathway and proinflammatory cytokine expression in established cell lines and primary cells from human and mouse. When administrated in colitis animal models, BBT-401 significantly improved colitis symptoms and histopathological parameters including ulceration, immune cell infiltration and re-epithelialization in both prophylactic and therapeutic settings. Especially when BBT-401 was directly administrated into colon, as low as 3mg/kg of BBT-401 showed considerable therapeutic efficacy. BBT-401 was not systemically absorbed following oral administrations and has been determined to be safe in GLP toxicology studies. Phase 1 clinical results showed that BBT-401 is safe with no systemic exposure, and well tolerated up to a single oral dose of 1600 mg and daily doses of 1600 mg for 7 days in healthy volunteers, with no severe adverse effect. BBT-401 is entering phase 2 clinical trial in active UC patients.