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

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Nat Commun. 2024 Dec 16;15(1):10683. doi: 10.1038/s41467-024-55006-2
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Development of a First-in-Class RIPK1 Degrader to Enhance Antitumor Immunity Wang (Meng) Lab
Yu Xin, Lu Dong, Qi Xiaoli, Lin Hanfeng, Holloman Bryan, Jin Feng, Xu Longyong, Ding Lang, Peng Weiyi, Wang Meng, Chen Xi, Wang Jin
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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 emerges as a promising target for improving cancer immunotherapies. To address the challenge posed by a poorly defined binding pocket within the intermediate domain of RIPK1, here we harness proteolysis targeting chimera (PROTAC) technology to develop a RIPK1 degrader, LD4172. LD4172 exhibits potent and selective RIPK1 degradation both in vitro and in vivo. Degradation of RIPK1 by LD4172 triggers immunogenic cell death, enhances tumor-infiltrating lymphocyte responses, and sensitizes tumors to anti-PD1 therapy in female C57BL/6J mice. This work reports a 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 ICBs therapy.

PMID: 39681571 [PubMed - indexed for MEDLINE]

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Previous bioRxiv preprint: https://doi.org/10.1101/2024.03.25.586133

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Janelia Authors

Lang Ding
Meng Wang
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