Structure-Based Optimization of Selective and Brain Penetrant CK1δ Inhibitors for the Treatment of Circadian Disruptions

被引：1

作者：

Mccarver, Stefan ^{[1
]}

Hanna, Luke ^{[1
]}

Samant, Andrew ^{[1
]}

Thompson, Aaron A. ^{[1
]}

Seierstad, Mark ^{[1
]}

Saha, Arjun ^{[1
]}

Wu, Dongpei ^{[1
]}

Lord, Brian ^{[1
]}

Sutton, Steven W. ^{[1
]}

Shah, Vishal ^{[1
]}

Milligan, Cynthia M. ^{[1
]}

Wennerholm, Michelle ^{[1
]}

Shelton, Jonathan ^{[1
]}

Lebold, Terry P. ^{[1
]}

Shireman, Brock T. ^{[1
]}

机构：

[1] Janssen Res & Dev, San Diego, CA 92121 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2024年 / 15卷 / 04期

关键词：

kinase inhibitor; casein kinase 1 delta; circadianrhythm; mood disorder; autoradiography; DISORDERS; RHYTHMS;

D O I：

10.1021/acsmedchemlett.3c00523

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 (CK1 delta) 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 CK1 delta versus the kinome. Pharmacokinetics, brain exposure, and target engagement as measured by ex vivo autoradiography are described for advanced analogs.

引用

收藏

页码：486 / 492

页数：7

相关论文

共 18 条

[1]

Butler T. W., 2012, Novel Fused Pyridine Compounds as Casein Kinase Inhibitors, Patent No. [US2012/0157440A1, 101021500201]

[2] Molecular mechanism of the repressive phase of the mammalian circadian clock [J].

Cao, Xuemei ;

Yang, Yanyan ;

Selby, Christopher P. ;

Liu, Zhenxing ;

Sancar, Aziz .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2021, 118 (02)

[3]

ClinicalTrials, SAF TOL PHARM BIIB 1

[4] Circadian rhythms in the CNS and peripheral clock disorders: Human sleep disorders and clock genes [J].

Ebisawa, Takashi .

JOURNAL OF PHARMACOLOGICAL SCIENCES, 2007, 103 (02) :150-154

[5] Casein Kinase 1 Delta (CK1δ) Regulates Period Length of the Mouse Suprachiasmatic Circadian Clock In Vitro [J].

Etchegaray, Jean-Pierre ;

Yu, Elizabeth A. ;

Indic, Premananda ;

Dallmann, Robert ;

Weaver, David R. .

PLOS ONE, 2010, 5 (04)

[6] Casein Kinase 1 Delta Regulates the Pace of the Mammalian Circadian Clock [J].

Etchegaray, Jean-Pierre ;

Machida, Kazuhiko K. ;

Noton, Elizabeth ;

Constance, Cara M. ;

Dallmann, Robert ;

Di Napoli, Marianne N. ;

DeBruyne, Jason P. ;

Lambert, Christopher M. ;

Yu, Elizabeth A. ;

Reppert, Steven M. ;

Weaver, David R. .

MOLECULAR AND CELLULAR BIOLOGY, 2009, 29 (14) :3853-3866

[7]

Langlois X, 2001, J PHARMACOL EXP THER, V299, P712

[8] A Small Molecule Modulates Circadian Rhythms through Phosphorylation of the Period Protein [J].

Lee, Jae Wook ;

Hirota, Tsuyoshi ;

Peters, Eric C. ;

Garcia, Michael ;

Gonzalez, Rodolfo ;

Cho, Charles Y. ;

Wu, Xu ;

Schultz, Peter G. ;

Kay, Steve A. .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2011, 50 (45) :10608-10611

[9] Crystal structure of a conformation-selective casein kinase-1 inhibitor [J].

Mashhoon, N ;

DeMaggio, AJ ;

Tereshko, V ;

Bergmeier, SC ;

Egli, R ;

Hoekstra, MF ;

Kuret, J .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (26) :20052-20060

[10] Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes [J].

Meng, Qing-Jun ;

Maywood, Elizabeth S. ;

Bechtold, David A. ;

Lu, Wei-Qun ;

Li, Jian ;

Gibbs, Julie E. ;

Dupre, Sandrine M. ;

Chesham, Johanna E. ;

Rajamohan, Francis ;

Knafels, John ;

Sneed, Blossom ;

Zawadzke, Laura E. ;

Ohren, Jeffrey F. ;

Walton, Kevin M. ;

Wager, Travis T. ;

Hastings, Michael H. ;

Loudon, Andrew S. I. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (34) :15240-15245