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bioRxiv · 10.1101/2024.03.25.586133

Development of a First-in-Class RIPK1 Degrader to Enhance Antitumor Immunity

Yu, X.·Lu, D.·Wang, J.
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Abstract

The scaffolding function of receptor interacting protein kinase 1 (RIPK1) confers intrinsic and extrinsic resistance to immune checkpoint blockades (ICBs) and has emerged as a promising target for improving cancer immunotherapies. To address the challenge posed by a poorly defined binding pocket within the intermediate domain, we harnessed proteolysis targeting chimera (PROTAC) technology to develop a first-in-class RIPK1 degrader, LD4172. LD4172 exhibited potent and selective RIPK1 degradation both in vitro and in vivo. Degradation of RIPK1 by LD4172 triggered immunogenic cell death (ICD) and enriched tumor-infiltrating lymphocytes and substantially sensitized the tumors to anti-PD1 therapy. This work reports the first RIPK1 degrader that serves as a chemical probe for investigating the scaffolding functions of RIPK1 and as a potential therapeutic agent to enhance tumor responses to immune checkpoint blockade therapy.

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Yu, X., Lu, D., Wang, J.. 2024-03-29. Development of a First-in-Class RIPK1 Degrader to Enhance Antitumor Immunity. https://doi.org/10.1101/2024.03.25.586133

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