8VXD

Structure of Casein kinase I isoform delta (CK1d) complexed with inhibitor 7

This is a non-PDB format compatible entry.

Summary for 8VXD

• Entry DOI: 10.2210/pdb8vxd/pdb
• Descriptor: Casein kinase I isoform delta, (4P)-4-[(3P)-3-(5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine (3 entities in total)
• Functional Keywords: ck1d, kinase, transferase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 70152.92

Authors

Thompson, A.A.,Milligan, C.M.,Sharma, S. (deposition date: 2024-02-04, release date: 2024-05-08)

Primary citation

McCarver, S.,Hanna, L.,Samant, A.,Thompson, A.A.,Seierstad, M.,Saha, A.,Wu, D.,Lord, B.,Sutton, S.W.,Shah, V.,Milligan, C.M.,Wennerholm, M.,Shelton, J.,Lebold, T.P.,Shireman, B.T.
Structure-Based Optimization of Selective and Brain Penetrant CK1 delta Inhibitors for the Treatment of Circadian Disruptions.
Acs Med.Chem.Lett., 15:486-492, 2024

PubMed 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 autoradiography are described for advanced analogs.

PubMed: 38628796
DOI: 10.1021/acsmedchemlett.3c00523

Experimental method

X-RAY DIFFRACTION (2.47 Å)