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 Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA.
Center for NextGen Therapeutics, Baylor College of Medicine, Houston, TX, USA.
Nat Commun. 2024 Dec 16;15(1):10683. doi: 10.1038/s41467-024-55006-2.
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.
受体相互作用蛋白激酶1（RIPK1）的支架功能赋予对免疫检查点阻断（ICB）的内在和外在抗性，并成为改善癌症免疫疗法的一个有前景的靶点。为了解决RIPK1中间结构域内结合口袋定义不明确所带来的挑战，我们在此利用蛋白酶靶向嵌合体（PROTAC）技术开发了一种RIPK1降解剂LD4172。LD4172在体外和体内均表现出高效且选择性的RIPK1降解作用。LD4172对RIPK1的降解引发免疫原性细胞死亡，增强肿瘤浸润淋巴细胞反应，并使雌性C57BL/6J小鼠的肿瘤对抗PD1治疗敏感。这项工作报道了一种RIPK1降解剂，其可作为研究RIPK1支架功能的化学探针以及增强肿瘤对ICB治疗反应的潜在治疗剂。
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