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 C Schuerer, 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

Research output: Contribution to journalArticle

29 Citations (Scopus)

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 languageEnglish
Pages (from-to)4374-4380
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number15
DOIs
StatePublished - Aug 1 2013

Fingerprint

Casein Kinase I
Cells
Lead compounds
Cell Line
Heterografts
Scaffolds
Inhibitory Concentration 50
Melanoma
Assays
Screening
Animals
Phosphotransferases
Throughput
Neoplasms

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

Cite this

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; Schuerer, Stephan C; 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 journalArticle

Bibian, M, Rahaim, RJ, Choi, JY, Noguchi, Y, Schuerer, SC, 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 ; Schuerer, Stephan C ; 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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