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

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

Molecular and Cellular Pharmacology

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

Abstract

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 ≤ 50 nM versus CK1δ. The two lead compounds have ≤100 nM 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.

Original language	English (US)
Pages (from-to)	4374-4380
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	23
Issue number	15
DOIs	https://doi.org/10.1016/j.bmcl.2013.05.075
State	Published - Aug 1 2013

Keywords

Antiproliferative agent
Casein kinase 1δ/ε inhibitor
Potent growth inhibitor of A375 melanoma cell line
Purine scaffold kinase inhibitor
Selective CK1δ/ε inhibitor

ASJC Scopus subject areas

Pharmaceutical Science
Drug Discovery
Organic Chemistry
Molecular Medicine
Molecular Biology
Clinical Biochemistry
Biochemistry

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Bibian, M., Rahaim, R. J., Choi, J. Y., Noguchi, Y., Schürer, S., Chen, W., Nakanishi, S., Licht, K., Rosenberg, L. H., Li, L., Feng, Y., Cameron, M. D., Duckett, D. R., Cleveland, J. L., & Roush, W. R. (2013). Development of highly selective casein kinase 1δ/1ε (CK1δ/ε) inhibitors with potent antiproliferative properties. Bioorganic and Medicinal Chemistry Letters, 23(15), 4374-4380. https://doi.org/10.1016/j.bmcl.2013.05.075

Development of highly selective casein kinase 1δ/1ε (CK1δ/ε) inhibitors with potent antiproliferative properties. / Bibian, Mathieu; Rahaim, Ronald J.; Choi, Jun Yong; Noguchi, Yoshihiko; Schürer, Stephan; Chen, Weimin; Nakanishi, Shima; Licht, Konstantin; Rosenberg, Laura H.; Li, Lin; Feng, Yangbo; Cameron, Michael D.; Duckett, Derek R.; Cleveland, John L.; Roush, William R.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 23, No. 15, 01.08.2013, p. 4374-4380.

Research output: Contribution to journal › Article › peer-review

Bibian, M, Rahaim, RJ, Choi, JY, Noguchi, Y, Schürer, S, Chen, W, Nakanishi, S, Licht, K, Rosenberg, LH, Li, L, Feng, Y, Cameron, MD, Duckett, DR, Cleveland, JL & Roush, WR 2013, 'Development of highly selective casein kinase 1δ/1ε (CK1δ/ε) inhibitors with potent antiproliferative properties', Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 15, pp. 4374-4380. https://doi.org/10.1016/j.bmcl.2013.05.075

Bibian, Mathieu ; Rahaim, Ronald J. ; Choi, Jun Yong ; Noguchi, Yoshihiko ; Schürer, Stephan ; Chen, Weimin ; Nakanishi, Shima ; Licht, Konstantin ; Rosenberg, Laura H. ; Li, Lin ; Feng, Yangbo ; Cameron, Michael D. ; Duckett, Derek R. ; Cleveland, John L. ; Roush, William R. / Development of highly selective casein kinase 1δ/1ε (CK1δ/ε) inhibitors with potent antiproliferative properties. In: Bioorganic and Medicinal Chemistry Letters. 2013 ; Vol. 23, No. 15. pp. 4374-4380.

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abstract = "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 ≤ 50 nM versus CK1δ. The two lead compounds have ≤100 nM 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.",

keywords = "Antiproliferative agent, Casein kinase 1δ/ε inhibitor, Potent growth inhibitor of A375 melanoma cell line, Purine scaffold kinase inhibitor, Selective CK1δ/ε inhibitor",

author = "Mathieu Bibian and Rahaim, {Ronald J.} and Choi, {Jun Yong} and Yoshihiko Noguchi and Stephan Sch{\"u}rer and Weimin Chen and Shima Nakanishi and Konstantin Licht and Rosenberg, {Laura H.} and Lin Li and Yangbo Feng and Cameron, {Michael D.} and Duckett, {Derek R.} and Cleveland, {John L.} and Roush, {William R.}",

note = "Funding Information: This research was supported by the NIH Molecular Library Screening Center Network grant U54MH074404 (Dr. Hugh Rosen, Principal Investigator), the Rendina Family Foundation, and funds from the State of Florida to Scripps Florida . S. Nakanishi was supported by a Marie Mayer Fellowship. ",

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AU - Schürer, Stephan

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AU - Rosenberg, Laura H.

AU - Li, Lin

AU - Feng, Yangbo

AU - Cameron, Michael D.

AU - Duckett, Derek R.

AU - Cleveland, John L.

AU - Roush, William R.

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