Structure-based optimization of GSK2982772-derived RIPK1 inhibitors reveals the dispensability of the methylene linker and identifies a potent anti-necroptosis candidate for further optimization

  • Eur J Med Chem. 2026 Jun 23:317:119077. doi: 10.1016/j.ejmech.2026.119077.
Yanran Wu  1 ,  Mengru Wu  2 ,  Jiale Wei  2 ,  Guojing Tao  2 ,  Yongkang Jia  2 ,  Huan Yang  3 ,  Qing Huang  2 ,  Ying Shi  4
Affiliations
  • 1. Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area (Ningxia Medical University), Ministry of Education, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China. Electronic address: [email protected].
  • 2. Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area (Ningxia Medical University), Ministry of Education, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China.
  • 3. General Hospital of Ningxia Medical University, China.
  • 4. Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area (Ningxia Medical University), Ministry of Education, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China. Electronic address: [email protected].
PMID: 42349361 DOI: 10.1016/j.ejmech.2026.119077
Abstract

Necroptosis is closely associated with a variety of inflammatory diseases, with receptor-interacting serine/threonine-protein kinase 1 (RIPK1) serving as a key regulator of this signaling pathway. RIPK1 inhibitors based on the 5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide scaffold have demonstrated potent anti-inflammatory activity, and two representatives, GSK2982772 and GSK3145095, advanced into Phase II clinical trials. However, their clinical development encountered significant challenges, highlighting the need for structurally novel RIPK1 inhibitors with improved pharmacological properties. Herein, GSK2982772 was selected as the starting point for rational optimization. Systematic structural modifications, including removal of the methylene linker in the benzyl moiety and replacement of the five-membered nitrogen-containing heterocycle with a phenyl ring, led to the design and synthesis of a series of novel biphenyl-based RIPK1 inhibitors. Importantly, our results demonstrate that the methylene linker is dispensable for anti-necroptosis activity and is not an essential pharmacophoric element in this scaffold. Among the synthesized compounds, W-1 exhibited approximately threefold stronger binding affinity toward RIPK1 than GSK2982772 (Kd = 21 nM vs. 60 nM). In addition to potent inhibition of Necroptosis in vitro, W-1 significantly attenuated inflammatory responses in a mouse systemic inflammatory response syndrome (SIRS) model. Furthermore, W-1 displayed lower cytotoxicity and reduced predicted interactions with more than 70 toxicity-associated targets, suggesting a potentially improved safety profile. Although its pharmacokinetic properties remain to be further optimized, W-1 represents a promising starting point for the development of next-generation RIPK1 inhibitors.

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