Discovery of pan-IAP degraders via a CRBN recruiting mechanism

Seulki Park; Dayoung Kim; Woori Lee; Jin Hwa Cho; Sungyoung Kim; Ga Seul Lee; Jeong Hee Moon; Jung-Ae Kim; Jae Du Ha; Jeong-Hoon Kim; Hyun Jin Kim

doi:10.1016/j.ejmech.2022.114910

Discovery of pan-IAP degraders via a CRBN recruiting mechanism

Eur J Med Chem. 2023 Jan 5;245(Pt 2):114910. doi: 10.1016/j.ejmech.2022.114910. Epub 2022 Nov 9.

Authors

Seulki Park¹, Dayoung Kim², Woori Lee³, Jin Hwa Cho¹, Sungyoung Kim⁴, Ga Seul Lee⁵, Jeong Hee Moon⁶, Jung-Ae Kim⁷, Jae Du Ha², Jeong-Hoon Kim⁸, Hyun Jin Kim⁹

Affiliations

¹ Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology KRIBB, Daejeon, 34141, South Korea.
² Data Convergence Drug Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, South Korea.
³ Data Convergence Drug Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, South Korea; Department of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 305-764, South Korea.
⁴ Critical Diseases Diagnostics Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology KRIBB, Daejeon, 34141, South Korea; Department of Proteome Structural Biology, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, 34113, South Korea.
⁵ Core Research Facility & Analysis Center, Korea Research Institute of Bioscience and Biotechnology KRIBB, Daejeon, 34141, South Korea; College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk, 28160, South Korea.
⁶ Core Research Facility & Analysis Center, Korea Research Institute of Bioscience and Biotechnology KRIBB, Daejeon, 34141, South Korea.
⁷ Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology KRIBB, Daejeon, 34141, South Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, 34113, South Korea; Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, South Korea.
⁸ Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology KRIBB, Daejeon, 34141, South Korea; Department of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 305-764, South Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, 34113, South Korea. Electronic address: jhoonkim@kribb.re.kr.
⁹ Data Convergence Drug Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, South Korea; Department of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 305-764, South Korea. Electronic address: hyunjin@krict.re.kr.

PMID: 36410083
DOI: 10.1016/j.ejmech.2022.114910

Abstract

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.

Keywords: CRBN; Caspase; EMT; Inhibitor of apoptosis (IAP); PROTAC; TD-1092.

MeSH terms

Apoptosis*
Cell Death
Cell Survival
Proteolysis
Signal Transduction*