4CGA

Human choline kinase a1 in complex with compound 5

Summary for 4CGA

• Entry DOI: 10.2210/pdb4cga/pdb
• Related: 4CG8 4CG9
• Descriptor: CHOLINE KINASE ALPHA, N,N-dimethyl-1-[[4-(2-phenylethyl)phenyl]methyl]pyridin-1-ium-4-amine (3 entities in total)
• Functional Keywords: transferase, cancer, drug target, biscationic compounds
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: P35790
• Total number of polymer chains: 1
• Total formula weight: 45271.90

Authors

Rubio-Ruiz, B.,Figuerola-Conchas, A.,Ramos-Torrecillas, J.,Capitan-Canadas, F.,Rios-Marco, P.,Carrasco, M.P.,Gallo, M.A.,Espinosa, A.,Marco, C.,Concepcion, C.,Entrena-Guadix, A.,Hurtado-Guerrero, R.,Conejo-Garcia, A. (deposition date: 2013-11-21, release date: 2014-01-15, Last modification date: 2023-12-20)

Primary citation

Rubio-Ruiz, B.,Figuerola-Conchas, A.,Ramos-Torrecillas, J.,Capitan-Canadas, F.,Rios-Marco, P.,Carrasco, M.P.,Gallo, M.A.,Espinosa, A.,Marco, C.,Concepcion, C.,Entrena-Guadix, A.,Hurtado-Guerrero, R.,Conejo-Garcia, A.
Discovery of a New Binding Site on Human Choline Kinase A1: Design, Synthesis, Crystallographic Studies and Biological Evaluation of Asymmetrical Bispyridinium Derivatives
J.Med.Chem., 57:507-, 2014

PubMed Abstract: Human choline kinase α (CKα) 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 CKα1 but also explains how these compounds induce apoptosis in cancer cells.

PubMed: 24387243
DOI: 10.1021/JM401665X

Experimental method

X-RAY DIFFRACTION (1.74 Å)