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1 Janelia Publications

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    Wang (Meng) Lab
    03/29/24 | Development of a First-in-Class RIPK1 Degrader to Enhance Antitumor Immunity
    Xin Yu , Dong Lu , Xiaoli Qi , Hanfeng Lin , Bryan L. Holloman , Feng Jin , Longyong Xu , Lang Ding , Weiyi Peng , Meng C. Wang , Xi Chen , Jin Wang
    bioRxiv. 2024 Mar 29:. doi: 10.1101/2024.03.25.586133

    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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