In vivo, 5e alleviated hypothermia and multi-organ injury in a mouse model of mTNF-α-induced systemic inflammatory response syndrome (SIRS). Although 5e retains some multi-kinase inhibitory activity, its improved RIPK1 potency and in vivo efficacy support further optimization.

Furthermore, combining IMMU132 with the PERK inhibitor GSK2606414 yields potent synergy across various CRC preclinical models. Mechanistically, this synergy stems from the enhanced suppression of ER stress and the oncogenic Wnt/β-catenin pathway. Thus, our findings reveal that co-targeting the DNA damage response, the PERK pathway, and the Wnt/β-catenin pathway is a promising strategy to overcome resistance to TROP2-directed antibody-drug conjugates (ADCs) in advanced CRC, providing a rational framework for combination therapies.

Notably, treatment with the PERK inhibitor GSK2606414 successfully reversed the UFL1 deficiency-induced upregulation of p-PERK, p-eIF2α, ATF4, and CHOP and rescued the apoptotic phenotype. Our study demonstrates for the first time that UFL1 is a critical regulator for maintaining myoblast survival and normal myofiber development, acting partly through suppressing the PERK-mediated ER sress. These findings provide novel insights into the pathogenesis of muscle developmental disorders and suggest UFL1 as a potential therapeutic target.

P2, N=164, Active, not recruiting, Eli Lilly and Company | Recruiting --> Active, not recruiting | N=380 --> 164 | Trial completion date: Jul 2026 --> Apr 2026

KSR1 knockdown did not substantially affect ppERK responses to Type I½ RAF inhibitor (Encorafenib) in both cell types, whereas ppERK sensitivity slightly decreased for Type II RAFi (TAK-632) in MCF7 cells, aligning with simulations. The efficacy of MEKi (Cobimetinib) slightly increased in MCF7 cells following KSR1 knockdown but slightly decreased in PSN1 cells where higher MEKi concentrations were required to suppress ERK signaling, as predicted by the model. Our computational models predict, and experiments validate that in RAS-mutant cells, two conformation-specific RAF inhibitors used in combination suppress the ERK pathway more effectively than a combination of MEK and RAF inhibitors irrespective of KSR1 levels.

P1, N=24, Recruiting, Accro Bioscience (Suzhou) Limited | Trial primary completion date: Dec 2025 --> Sep 2026

P2, N=67, Terminated, Genentech, Inc. | N=404 --> 67 | Active, not recruiting --> Terminated; Unlikely to demonstrate a statistically significant clinical benefit

P2, N=404, Active, not recruiting, Genentech, Inc. | Recruiting --> Active, not recruiting

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitors are being investigated for chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis...In a phase 1, double-blind, randomized, multiple-dose study in healthy participants, greater than 90% RIPK1 target engagement was achieved at Day 14 with ocadusertib treatment. Taken together, these findings support further assessment of ocadusertib for the treatment of chronic inflammatory diseases.

P2, N=404, Recruiting, Genentech, Inc. | Trial primary completion date: Nov 2027 --> Mar 2026 | Trial completion date: Nov 2027 --> Mar 2026

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