Notably, Several RIPK1 inhibitors (e.g., DNL-788, DNL-758, R-552) have advanced to Phase II clinical trials for indications like multiple sclerosis, ulcerative colitis, and rheumatoid arthritis. Despite these advancements, the field continues to face challenges, particularly the need for chemical scaffold design and therapeutic strategies to address two longstanding challenges: off-target effects and enhancing blood-brain barrier (BBB) penetration. This review systematically summarizes the development history of regulators targeting this pathway, covering emerging multitarget inhibitors, bifunctional molecules, and AI-driven drug design progress, laying an important foundation for related drug discovery research.

P2, N=187, Active, not recruiting, Sanofi | Recruiting --> Active, not recruiting

P1, N=68, Completed, Sanofi | Phase classification: P1b --> P1

P1, N=15, Terminated, Sanofi | Phase classification: P1b --> P1

These findings underscore the promise of GSK2606414 and cisplatin co-treatment as a potent strategy to counteract ovarian cancer resistance. This combination could potentially advance therapeutic outcomes and provide a new pharmacological approach to resistant cancers.

P1, N=24, Recruiting, Accro Bioscience (Suzhou) Limited

Transcriptomic studies were carried out using USC Xena and R, while in vitro assays were performed with the glioblastoma human cell line U251 and the commercial RIPK1 inhibitor GSK2982772...To further characterize the role of RIPK1 in DG, the effects of the RIPK1 inhibitor were evaluated, alone or combined with cisplatin, on glioblastoma cell proliferation and apoptosis. The combined treatments effectively reduced cell proliferation and increased apoptosis. The overexpression of RIPK1 was associated with a poor prognosis for DG, suggesting that RIPK1 plays a critical role in glioma pathogenesis and should be considered in therapeutic decision-making.

This was characterized by heightened necroptosis activation, reduced cell viability, and increased apoptosis. These findings expand our understanding of the interaction between DNA damage and cell death regulation and may aid in developing therapeutic drugs to enhance DNA damage-induced tumor necroptosis and improve chemosensitivity.

P1, N=7, Completed, Genentech, Inc. | Terminated --> Completed

This was characterized by heightened necroptosis activation, reduced cell viability, and increased apoptosis. These findings expand our understanding of the interaction between DNA damage and cell death regulation and may aid in developing therapeutic drugs to enhance DNA damage-induced tumor necroptosis and improve chemosensitivity.

P2, N=182, Recruiting, Sanofi | Trial completion date: Sep 2026 --> Dec 2026 | Trial primary completion date: Nov 2025 --> Feb 2026

P2, N=404, Recruiting, Genentech, Inc. | Not yet recruiting --> Recruiting