2. Academic Validation
  3. Synthesis and identification of unprecedented selective inhibitors of CK1ε

Synthesis and identification of unprecedented selective inhibitors of CK1ε

  • Eur J Med Chem. 2015:96:308-17. doi: 10.1016/j.ejmech.2015.03.046.
Gastón Silveira-Dorta 1,  Inês J Sousa 2,  Miguel X Fernandes 3,  Victor S Martín 1,  José M Padrón 4
Affiliations

Affiliations

  • 1 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.
  • 2 Centro de Química da Madeira, Centro de Ciências Exatas e da Engenharia, Universidade da Madeira, Campus da Penteada, 9020-105 Funchal, Portugal.
  • 3 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.
  • 4 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. Electronic address: jmpadron@ull.es.
PMID: 25899335 DOI: 10.1016/j.ejmech.2015.03.046
Abstract

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.

Keywords

Antitumor agents; Casein kinase 1 epsilon; Enzyme inhibitors; Sphingoid bases; Target fishing.

Figures