Development of a RIPK1 degrader to enhance antitumor immunity.

Yu, Xin; Lu, Dong; Qi, Xiaoli; Paudel, Rishi Ram; Lin, Hanfeng; Holloman, Bryan L.; Jin, Feng; Xu, Longyong; Ding, Lang; Peng, Weiyi; Wang, Meng C.; Chen, Xi; Wang, Jin

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. It has been shown that targeting receptor-interacting protein kinase 1 (RIPK1) can improve response to immune checkpoint inhibitors. Here, using PROTAC technology, the authors report the design and characterization of a RIPK1 degrader, enhancing anti-tumor immunity in preclinical cancer models.

RECEPTOR-interacting proteins; MEDICAL sciences; IMMUNE checkpoint proteins; IMMUNE checkpoint inhibitors; LIFE sciences

Nature Communications, 2024, Vol 15, Issue 1, p1

2041-1723

Academic Journal

10.1038/s41467-024-55006-2