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 |
|---|---|
| Pages (from-to) | 4374-4380 |
| Number of pages | 7 |
| Journal | Bioorganic and Medicinal Chemistry Letters |
| Volume | 23 |
| Issue number | 15 |
| DOIs | |
| State | Published - Aug 1 2013 |
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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 journal › Article
}
TY - JOUR
T1 - Development of highly selective casein kinase 1δ/1ε (CK1δ/ε) inhibitors with potent antiproliferative properties
AU - Bibian, Mathieu
AU - Rahaim, Ronald J.
AU - Choi, Jun Yong
AU - Noguchi, Yoshihiko
AU - Schuerer, Stephan C
AU - Chen, Weimin
AU - Nakanishi, Shima
AU - Licht, Konstantin
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.
PY - 2013/8/1
Y1 - 2013/8/1
N2 - 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.
AB - 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.
KW - Antiproliferative agent
KW - Casein kinase 1δ/ε inhibitor
KW - Potent growth inhibitor of A375 melanoma cell line
KW - Purine scaffold kinase inhibitor
KW - Selective CK1δ/ε inhibitor
UR - http://www.scopus.com/inward/record.url?scp=84879693358&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84879693358&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2013.05.075
DO - 10.1016/j.bmcl.2013.05.075
M3 - Article
C2 - 23787102
AN - SCOPUS:84879693358
VL - 23
SP - 4374
EP - 4380
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 15
ER -