Discovery of a New Binding Site on Human Choline Kinase alpha 1: Design, Synthesis, Crystallographic Studies, and Biological Evaluation of Asymmetrical Bispyridinium Derivatives

• Published in: Journal of medicinal chemistry Vol. 57; no. 2; pp. 507 - 515
• Main Authors: Rubio-Ruiz, Belen, Figuerola-Conchas, Ainoa, Ramos-Torrecilas, Javier, Capitan-Canadas, Fermin, Rios-Marco, Pablo, Paz Carrasco, Ma, Angel Gallo, Miguel, Espinosa, Antonio, Marco, Carmen, Ruiz, Concepcion, Entrena, Antonio, Hurtado-Guerrero, Ramon, Conejo-Garcia, Ana
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 23.01.2014
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; APOPTOSIS; ISOFORMS; INHIBITORS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm401665x

Human choline kinase alpha (CK alpha) is a validated drug target for the treatment of cancer. In recent years, a large number of CK inhibitors have been synthesized, and one of them is currently being evaluated in Phase I clinical trials as a treatment for solid tumors. Here we have evaluated a new series of asymmetrical biscationic CK inhibitors by means of enzymatic, crystallographic, and antitumor studies. We demonstrate that one of these structures adopts a completely new binding mode not observed before inducing the aperture of an adjacent binding site. This compound shows antiproliferative and apoptotic effects on cancer cells through activation of caspase-3. Therefore, this study not only provides fruitful insights into the design of more efficient compounds that may target different regions in CK alpha 1 but also explains how these compounds induce apoptosis in cancer cells.