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Identification of Potent and Selective RIPK2 Inhibitors for the Treatment of Inflammatory Diseases

He, Xiaohui, DaRos, Sara, Zhu, Xuefeng, Nelson, John, Michellys, Pierre, Iskandar, Maya, Espinola, Sheryll, Bursulaya, Badry, Gao, Mu-Yun, Kreusch, Andreas, Baaten, Janine, Clemmer, Leah, Meeusen, Shelly, Huang, David, Hill, Robert, Nguyen-Tran, Van, Fathman, John, Liu, Bo, Tuntland, Tove, Ng, Kenneth, Shi, Jian, Bordone, Laura and Liu, Hong (2017) Identification of Potent and Selective RIPK2 Inhibitors for the Treatment of Inflammatory Diseases. ACS Medicinal Chemistry Letters. ISSN 1948-58751948-5875


NOD2 (nucleotide-binding oligomerization domain-containing proteins 2) is an essential regulator of immunologic mucosal homeostasis. Malfunction of NOD2 causes auto inflammatory disorders including Crohn’s Disease and Ulcerative Colitis. Receptor interacting protein kinase 2 (RIPK2) is an intracellular serine/threonine/tyrosine kinase and key signaling partner for NOD2. As such, RIPK2 represents an attractive target to probe the role of the pathway in these diseases. Inhibition of RIPK2 might alleviate auto-inflammatory disorders in which NOD2:RIPK2 activity is aberrantly high. To search for selec-tive RIPK2 inhibitors, data mining of VLS led to the identification of hit 1. Structure based design eventually led to potent and selective RIPK2 inhibitor 8 with excellent oral bioavailability which was used to evaluate effect of inhibition of RIPK2 in various in vitro, ex vivo and in vivo PD models.

Item Type: Article
Keywords: RIPK2, NOD2, kinase inhibitors, structure-based drug design
Date Deposited: 21 Oct 2017 00:45
Last Modified: 21 Oct 2017 00:45


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