Development of a RIPK1 degrader to enhance antitumor immunity

Xin Yu, Dong Lu (), Xiaoli Qi, Rishi Ram Paudel, Hanfeng Lin, Bryan L. Holloman, Feng Jin, Longyong Xu, Lang Ding, Weiyi Peng, Meng C. Wang, Xi Chen and Jin Wang ()
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Xin Yu: Baylor College of Medicine
Dong Lu: Baylor College of Medicine
Xiaoli Qi: Baylor College of Medicine
Rishi Ram Paudel: Baylor College of Medicine
Hanfeng Lin: Baylor College of Medicine
Bryan L. Holloman: Baylor College of Medicine
Feng Jin: Baylor College of Medicine
Longyong Xu: Baylor College of Medicine
Lang Ding: Janelia Research Campus
Weiyi Peng: University of Houston
Meng C. Wang: Janelia Research Campus
Xi Chen: Baylor College of Medicine
Jin Wang: Baylor College of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-55006-2

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