Department of Chemistry, Scripps Florida, 130 Scripps Way, Jupiter, FL 33458, United States.
Bioorg Med Chem Lett. 2013 Aug 1;23(15):4374-80. doi: 10.1016/j.bmcl.2013.05.075. Epub 2013 May 31.
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.
本文描述了一系列强效且高选择性的酪蛋白激酶 1δ/ε（CK1δ/ε）抑制剂的开发。从高通量筛选中鉴定出的嘌呤骨架抑制剂（SR-653234）出发，我们开发了一系列强效且高激酶选择性抑制剂，包括 SR-2890 和 SR-3029，它们对 CK1δ 的 IC₅₀≤50 nM。这两个先导化合物在 MTT 测定中对人 A375 黑色素瘤细胞系的 EC50 值均≤100 nM，具有适合用于针对人癌细胞系的原理验证动物异种移植研究的物理、体外和体内 PK 特性。
