Instituto Universitario de Bio-Orgánica "Antonio González" (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, C/ Astrofísico Francisco Sánchez 2, 38206 La Laguna, Spain.
Centro de Química da Madeira, Centro de Ciências Exatas e da Engenharia, Universidade da Madeira, Campus da Penteada, 9020-105 Funchal, Portugal.
Eur J Med Chem. 2015;96:308-17. doi: 10.1016/j.ejmech.2015.03.046. Epub 2015 Apr 14.
A small and structure-biased library of enantiopure anti-β-amino alcohols was prepared in a straightforward manner by a simplified version of the Reetz protocol. Antiproliferative activity testing against a panel of five human solid tumor cell lines gave GI50 values in the range 1-20 μM. The reverse screening by computational methods against 58 proteins involved in cancer pointed to kinases as possible therapeutic target candidates. The experimental determination of the interaction with 456 kinases indicated that the compounds behave as selective CK1ε inhibitors. Our results demonstrate that the lead compound represents the first selective CK1ε inhibitor with proven antiproliferative activity in cancer cell lines.
采用简化的 Reetz 法，以简单直接的方式制备了小的、结构偏向的对映体纯的反-β-氨基醇库。对五个人类实体瘤细胞系的抗增殖活性测试得到 GI50 值在 1-20 μM 的范围内。通过计算方法对涉及癌症的 58 种蛋白质进行反向筛选，结果表明激酶可能是潜在的治疗靶点候选物。与 456 种激酶的实验测定表明，这些化合物表现为选择性 CK1ε 抑制剂。我们的研究结果表明，该先导化合物代表了首个具有选择性 CK1ε 抑制活性和在癌细胞系中证实的抗增殖活性的 CK1ε 抑制剂。
