Discovery of pan-IAP degraders via a CRBN recruiting mechanism

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Discovery of pan-IAP degraders via a CRBN recruiting mechanism
Seulki Park; D Kim; W Lee; Jin Hwa Cho; Sungyoung Kim; Ga Seul Lee; Jeong Hee MoonJung Ae Kim; J D Ha; Jeong Hoon Kim; H J Kim
Bibliographic Citation
European Journal of Medicinal Chemistry, vol. 245, no. 2, pp. 114910-114910
Publication Year
Inhibitors of apoptosis proteins (IAPs), defined by the presence of baculovirus IAP repeat (BIR) protein domain, are critical regulators of cell survival and cell death processes. Cellular IAP 1/2 (cIAP1/2) and X-linked IAPs (XIAPs) regulate the innate immune signaling pathway through their E3 ubiquitin ligase activity. Peptidomimetics or small-molecule IAP antagonists have been developed to treat various diseases, such as cancer, infection, and inflammation. In this study, we synthesized and characterized IAP?cereblon (CRBN) heterodimerizing proteolysis-targeting chimera (PROTAC), which induces the degradation of cIAP1/2 and XIAP but not CRBN. We demonstrated that this PROTAC inhibits tumor necrosis factor alpha (TNFα)-induced innate immune response and cancer cell migration and invasion, leading to apoptotic cell death. Our study is the first to demonstrate that both cIAPs and XIAP are degradable when applied to the PROTAC strategy.
Inhibitor of apoptosis (IAP)CRBNPROTACCaspaseEMTTD-1092
Appears in Collections:
Division of Biomedical Research > Disease Target Structure Research Center > 1. Journal Articles
Division of Bio Technology Innovation > Core Research Facility & Analysis Center > 1. Journal Articles
Aging Convergence Research Center > 1. Journal Articles
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