Early Development of Ocadusertib, a Selective Receptor-Interacting Serine/Threonine-Protein Kinase 1 Inhibitor
Simon J Shaw1, Vanessa C Taylor1, Jonathan T Sims2
1Rigel Pharmaceuticals, Inc., South San Francisco, California, USA.
Clinical and Translational Science
|March 6, 2026
Summary
Ocadusertib, a potent Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitor, shows promise for chronic inflammatory diseases. Phase 1 trials demonstrate good tolerability, target engagement, and favorable pharmacokinetics in humans.
Area of Science:
- Pharmacology
- Immunology
- Drug Development
Background:
- Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitors are explored for chronic inflammatory conditions like rheumatoid arthritis, inflammatory bowel disease, and psoriasis.
- Ocadusertib is a selective, allosteric RIPK1 inhibitor currently in clinical trials.
Purpose of the Study:
- To present preclinical and Phase 1 clinical data on ocadusertib development.
- To evaluate its pharmacokinetic, safety, and target engagement profiles.
Main Methods:
- Preclinical studies assessed ocadusertib's enzymatic and cellular activity, selectivity, and in vivo efficacy in mouse models.
- Phase 1 trials in healthy participants evaluated pharmacokinetics, safety, tolerability, and RIPK1 target engagement after single and multiple doses.
Main Results:
- Ocadusertib demonstrated potent RIPK1 inhibition (IC50: 12-38 nM) and blocked necroptotic responses.
- It showed high selectivity for RIPK1 and reduced disease severity in mouse models.
- Phase 1 trials revealed linear pharmacokinetics, dose-proportional exposure, and good tolerability with over 90% RIPK1 target engagement by Day 14.
Conclusions:
- Ocadusertib exhibits favorable preclinical and early clinical profiles.
- These findings support further investigation of ocadusertib for treating chronic inflammatory diseases.
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