Development of highly selective casein kinase 1δ/1ε (CK1δ/ε) inhibitors with potent antiproliferative properties

Mathieu Bibian; Ronald J Rahaim; Jun Yong Choi; Yoshihiko Noguchi; Stephan Schürer; Weimin Chen; Shima Nakanishi; Konstantin Licht; Laura H Rosenberg; Lin Li; Yangbo Feng; Michael D Cameron; Derek R Duckett; John L Cleveland; William R Roush

doi:10.1016/j.bmcl.2013.05.075

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Development of highly selective casein kinase 1δ/1ε (CK1δ/ε) inhibitors with potent antiproliferative properties

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Development of highly selective casein kinase 1δ/1ε (CK1δ/ε) inhibitors with potent antiproliferative properties

Mathieu Bibian, Ronald J Rahaim, Jun Yong Choi, Yoshihiko Noguchi, Stephan Schürer, Weimin Chen, Shima Nakanishi, Konstantin Licht, Laura H Rosenberg, Lin Li, …

Bioorganic & medicinal chemistry letters, Vol.23(15), pp.4374-4380

2013-08-01

DOI: https://doi.org/10.1016/j.bmcl.2013.05.075

PMCID: PMC3783656

PMID: 23787102

Abstract

Purine scaffold kinase inhibitor

Antiproliferative agent

Casein kinase 1δ/ε inhibitor

Selective CK1δ/ε inhibitor

Potent growth inhibitor of A375 melanoma cell line

The development of a series of potent and highly selective casein kinase 1δ/ε (CK1δ/ε) inhibitors is described. Starting from a purine scaffold inhibitor (SR-653234) identified by high throughput screening, we developed a series of potent and highly kinase selective inhibitors, including SR-2890 and SR-3029, which have IC50⩽50nM versus CK1δ. The two lead compounds have ⩽100nM EC50 values in MTT assays against the human A375 melanoma cell line and have physical, in vitro and in vivo PK properties suitable for use in proof of principle animal xenograft studies against human cancer cell lines.

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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.108 Molecular & Cell Biology - Cancer & Development; 1.108.757 Beta-Catenin
Web Of Science research areas: Chemistry, Medicinal; Chemistry, Organic
ESI research areas: Chemistry

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Title: Development of highly selective casein kinase 1δ/1ε (CK1δ/ε) inhibitors with potent antiproliferative properties
Creators: Mathieu Bibian - Department of Chemistry, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, United States
Ronald J Rahaim - Department of Chemistry, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, United States
Jun Yong Choi - Department of Chemistry, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, United States
Yoshihiko Noguchi - Department of Chemistry, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, United States
Stephan Schürer - Department of Molecular and Cellular Pharmacology and Center for Computational Science, University of Miami, 1120 NW 14th St., Miami, FL 33136, United States
Weimin Chen - Department of Molecular Therapeutics, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, United States
Shima Nakanishi - Department of Cancer Biology, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, United States
Konstantin Licht - Department of Cancer Biology, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, United States
Laura H Rosenberg - Department of Molecular Therapeutics, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, United States
Lin Li - Department of Molecular Therapeutics, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, United States
Yangbo Feng - Department of Chemistry, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, United States
Michael D Cameron - Department of Molecular Therapeutics, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, United States
Derek R Duckett - Department of Molecular Therapeutics, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, United States
John L Cleveland - Department of Cancer Biology, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, United States
William R Roush - Department of Chemistry, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, United States
Publication Details: Bioorganic & medicinal chemistry letters, Vol.23(15), pp.4374-4380
Publisher: Elsevier Ltd
Academic Unit: Miller School of Medicine; Molecular and Cellular Pharmacology Research
Language: English
Resource Type: Journal article
PMID: 23787102
PMCID: PMC3783656
Record Identifier: 991031559233302976