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Receptor-interacting protein kinase 2 (RIPK2) is a serine/threonine kinase that has been extensively studied in inflammation and innate immunity, mainly acting through the NOD/RIPK2/NF-kB or MAPK signal transduction pathway. RIPK2 plays a vital role in the inflammatory signaling cascade of NOD1/2, which are receptors responsible for bacterial recognition, thereby stimulating both pro-inflammatory and antimicrobial responses. Increased RIPK2 activity is associated with inflammatory bowel diseases and various chronic inflammatory disorders.
AC-101,a highly potent and selective oral small molecule inhibitor of RIPK2, showed therapeutic benefits in both mouse and rat models of inflammatory bowel disease.
In Phase I study, AC-101 displayed favorable PK characteristics with robust RIPK2 inhibition. AC-101 was safe and well-tolerated with no serious adverse events in healthy subjects. Phase Ib/2 clinical trial of AC-101 in patients with inflammatory bowel diseases is about to commence.
Inflammatory Bowel Disease, IBD
Inflammatory bowel disease (IBD) is a chronic nonspecific inflammatory disease of the intestine, including Ulcerative Colitis (UC) and Crohn's Disease (CD)[8]. Genetic susceptibility, intestinal mucosal immune abnormalities considered as internal factors and environmental influences, changes in diet and lifestyle, as well as alterations in the gut microbiota seen as important external factors. The interaction between internal and external factors leads to the occurrence of the disease[9].
Inflammatory bowel disease (IBD) has become a global disease, with incidence and prevalence increasing gradually across different regions[10].
Although multiple biologics and novel small molecule drugs have improved the treatment and management of Ulcerative Colitis (UC) and Crohn's Disease (CD)[11], these therapies are only effective for a portion of IBD patients and prone to loss of efficacy. Additionally, there are some safety concerns, with an increased risk of serious adverse events (such as severe infections and cardiovascular events) and malignancies. There is a need to further develop drugs for sustained remission of IBD, preventing disease progression and disability.
[8] Dai C, Huang YH, Jiang M. Combination therapy in inflammatory bowel disease: Current evidence and perspectives. Int Immunopharmacol. 2023;114:109545.
[9] 李学锋,彭霞,周明欢.我国炎症性肠病流行病学研究进展[J].现代消化及介入诊疗, 2020, 25(9):3.
[10] Bernstein CN, Eliakim A, Fedail S, et al. World Gastroenterology Organisation Global Guidelines Inflammatory Bowel Disease: Update August 2015. J Clin Gastroenterol. 2016;50(10):803-818.
[11] Chang S, Murphy M, Malter L. A Review of Available Medical Therapies to Treat Moderate-to-Severe Inflammatory Bowel Disease. Am J Gastroenterol. 2024;119(1):55-80.
