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    DRUG CLASS:

    RIPK1 inhibitor

    Related drugs:
    6d
    Dual RAF inhibition outperforms RAF-MEK combinations for suppressing ERK signaling in KRAS mutant cells. (PubMed, NPJ Syst Biol Appl)
    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.
    Journal
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    KRAS (KRAS proto-oncogene GTPase)
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    KRAS mutation • KRAS wild-type • RAS mutation • KRAS G12R
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    Cotellic (cobimetinib) • Braftovi (encorafenib) • TAK‐632
    1m
    A Phase Ib Clinical Study of AC-003 Capsules in Subjects With aGVHD. (clinicaltrials.gov)
    P1, N=24, Recruiting, Accro Bioscience (Suzhou) Limited | Trial primary completion date: Dec 2025 --> Sep 2026
    Trial primary completion date
    1m
    A Study to Evaluate the Efficacy and Safety of GDC-8264 in Preventing Cardiac Surgery-Associated Acute Kidney Injury (AKI) and Major Adverse Kidney Events (MAKE) (clinicaltrials.gov)
    P2, N=67, Terminated, Genentech, Inc. | N=404 --> 67 | Active, not recruiting --> Terminated; Unlikely to demonstrate a statistically significant clinical benefit
    Enrollment change • Trial termination • Adverse events
    1m
    A Study to Evaluate the Efficacy and Safety of GDC-8264 in Preventing Cardiac Surgery-Associated Acute Kidney Injury (AKI) and Major Adverse Kidney Events (MAKE) (clinicaltrials.gov)
    P2, N=404, Active, not recruiting, Genentech, Inc. | Recruiting --> Active, not recruiting
    Enrollment closed • Adverse events
    2ms
    Early Development of Ocadusertib, a Selective Receptor-Interacting Serine/Threonine-Protein Kinase 1 Inhibitor. (PubMed, Clin Transl Sci)
    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.
    Journal • First-in-human
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    TNFA (Tumor Necrosis Factor-Alpha) • CDK7 (Cyclin Dependent Kinase 7) • RIPK1 (Receptor Interacting Serine/Threonine Kinase 1)
    2ms
    A Study to Evaluate the Efficacy and Safety of GDC-8264 in Preventing Cardiac Surgery-Associated Acute Kidney Injury (AKI) and Major Adverse Kidney Events (MAKE) (clinicaltrials.gov)
    P2, N=404, Recruiting, Genentech, Inc. | Trial primary completion date: Nov 2027 --> Mar 2026 | Trial completion date: Nov 2027 --> Mar 2026
    Trial completion date • Trial primary completion date • Adverse events
    3ms
    Small-molecule modulators of the necroptotic pathway: A medicinal chemistry perspective. (PubMed, Eur J Med Chem)
    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.
    Review • Journal
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    RIPK1 (Receptor Interacting Serine/Threonine Kinase 1)
    3ms
    RESOLUTE: Dose-finding Study of SAR443122 in Adult Participants With Ulcerative Colitis (clinicaltrials.gov)
    P2, N=187, Active, not recruiting, Sanofi | Recruiting --> Active, not recruiting
    Enrollment closed
    7ms
    A Phase 1b Trial to Evaluate Safety and Effect of SAR443122 on Immune System in Severe COVID-19 (clinicaltrials.gov)
    P1, N=68, Completed, Sanofi | Phase classification: P1b --> P1
    Phase classification
    7ms
    Study to Evaluate DNL747 in Subjects With Amyotrophic Lateral Sclerosis (clinicaltrials.gov)
    P1, N=15, Terminated, Sanofi | Phase classification: P1b --> P1
    Phase classification
    9ms
    Targeting the PERK/NRF2 Pathway: Enhancing cisplatin Efficacy in Resistant Ovarian Cancer Cells through MRP1 and ROS Modulation. (PubMed, Food Chem Toxicol)
    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.
    Journal
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    MSH3 (MutS Homolog 3) • CASP12 (Caspase 12 (Gene/Pseudogene))
    |
    cisplatin • GSK2606414
    9ms
    A Phase Ib Clinical Study of AC-003 Capsules in Subjects With Steroid-refractory aGVHD. (clinicaltrials.gov)
    P1, N=24, Recruiting, Accro Bioscience (Suzhou) Limited
    New P1 trial