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Updated: Jun 28, 2025

Author Spotlight: In Vitro Investigations of Circadian Rhythms in Multicellular Systems
Published on: February 16, 2024
Structure-Based Optimization of Selective and Brain Penetrant CK1δ Inhibitors for the Treatment of Circadian
Stefan McCarver1, Luke Hanna1, Andrew Samant1
1Janssen Research and Development, San Diego, California 92121-1126, United States.
Abstract:
Neuropsychiatric disorders such as major depressive disorders and schizophrenia are often associated with disruptions to the normal 24 h sleep wake cycle. Casein kinase 1 (CK1δ) is an integral part of the molecular machinery that regulates circadian rhythms. Starting from a cluster of bicyclic pyrazoles identified from a virtual screening effort, we utilized structure-based drug design to identify and reinforce a unique "hinge-flip" binding mode that provides a high degree of selectivity for CK1δ versus the kinome. Pharmacokinetics, brain exposure, and target engagement as measured by ex vivo autoradiography are described for advanced analogs.
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