Scholarlink

<p>Cancer cells can hijack receptor-interacting protein kinase 1 (RIPK1) and exploit its scaffolding function to orchestrate pro-survival signaling and fuel immunosuppressive program. Accordingly, targeting RIPK1 for elimination has emerged as a promising anti-cancer strategy. Based on the RIPK1 inhibitor <b>4</b> previously reported by our group, we employed proteolysis targeting chimera (PROTAC) technology and designed a series of RIPK1 degraders. Structure–activity relationship (SAR) study revealed three types of ligands for E3 ligase — cereblon (CRBN), von Hippel-Lindau (VHL) and inhibitor of apoptosis protein (IAP) — demonstrated varied efficacy in RIPK1 degradation of human and mouse cells. The VHL-based compound <b>18</b> exhibited potent RIPK1 degradation activity in both human and mouse cellular scenarios. Further biological evaluation confirmed that compound <b>18</b> potently induced RIPK1 degradation of I2.1 cells with a DC<sub>50</sub> value of 274.4&#xa0;nM and maintained long-term and dramatic RIPK1 degradation within 72&#xa0;h. This study provided important insights into future development of RIPK1-PORTACs, and compound <b>18</b> was a promising RIPK1 degrader candidate.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Design, synthesis, and biological evaluation of RIPK1-targeting PROTACs

  • 期刊论文

  • 发表日期：

    2025年3月24日

查看全文
  • Hefeng Zhang,
  • Shuonan Zhang,
  • Tianchen Wang,
  • Yaohan Lan,
  • Yang Dai,
  • Xia Peng,
  • Yuxiang An,
  • Yi Xue,
  • Jing Ai,
  • Wenhu Duan

摘要

Cancer cells can hijack receptor-interacting protein kinase 1 (RIPK1) and exploit its scaffolding function to orchestrate pro-survival signaling and fuel immunosuppressive program. Accordingly, targeting RIPK1 for elimination has emerged as a promising anti-cancer strategy. Based on the RIPK1 inhibitor 4 previously reported by our group, we employed proteolysis targeting chimera (PROTAC) technology and designed a series of RIPK1 degraders. Structure–activity relationship (SAR) study revealed three types of ligands for E3 ligase — cereblon (CRBN), von Hippel-Lindau (VHL) and inhibitor of apoptosis protein (IAP) — demonstrated varied efficacy in RIPK1 degradation of human and mouse cells. The VHL-based compound 18 exhibited potent RIPK1 degradation activity in both human and mouse cellular scenarios. Further biological evaluation confirmed that compound 18 potently induced RIPK1 degradation of I2.1 cells with a DC50 value of 274.4 nM and maintained long-term and dramatic RIPK1 degradation within 72 h. This study provided important insights into future development of RIPK1-PORTACs, and compound 18 was a promising RIPK1 degrader candidate.