Colina cinasa inhibitors with anticancer activity
The inhibitors collected in the invention refer to symmetrical polar compounds of bispyridine, bisquinuclidine and bisquinoline, with a linker derived from 1,2bis(p-tolyloxy)ethane choline kinase inhibitors, their synthesis and their use as an anticancer drug. These compounds have been tested on nine cell lines showing a large amount of activity and being effective both on solid and liquid or leukaemic tumours.
The choline kinase enzyme (ChoK) is the first enzyme of the CDP-choline or Kennedy pathway, which permits the biosynthesis of phosphatidylcholine (PC), a majority phospholipid of cell membranes. This enzyme catalyses the phosphorylation of choline to phosphocholine (PCho) using ATP and Mg2+ as a cofactor. In cancerous conditions, different oncogenes like src, but mainly the ras oncogen, provoke an excess of ChoK activity, which translates into an increase in intracellular PCho levels, without the existence of cooperation with PC biosynthesis.
The employment of nuclear magnetic resonance (NMR) techniques applied on different human tumours (breast, lung, colon, colorectal, prostate and hepatic lymphoma, amongst others) has enabled it to be corroborated that in all of them there is a notable increase in PCho levels with regards to existing levels in the corresponding healthy tissue. Due to the important role played by ChoK and PCho in human carcinogenesis, ChoK has become a perfect therapeutic target for the design of anticancer drugs, capable of selectively inhibiting the enzyme, avoiding the production of PCho and, therefore, the mitogenic activity associated with this metabolite. In this sense, at present there are only three specific drugs in the world for this same target at the advanced clinical stage.
In light of the biological results obtained in this invention, it is proposed that these Chok inhibitors may constitute a prototype for the design of new drugs in the treatment of cancer.
These compounds show biological activity as inhibitors of the human ChoK enzyme, as well as antiproliferative activity against the following tumour pathways: HeLa human cervix carcinoma; HT-29 colon adenocarcinoma; Jurkat human leukaemic T-cell; HL-60 promyelocytic leukemia; human RS4 B-cell leukemia; MCF-7 breast carcinoma, PC-3 prostate carcinoma, A549 non-microcitic lung carcinoma, and the drug-resistent HepG2 human heptoma cell line.
Licence agreement for operation and/or collaboration.
Sectors of application: Chemistry, Pharmacy, Healthcare.
Stage of development: Patent, PCT requested.
Priority date: 11/05/2015.
Owner: University of Granada and University of Padua (Italy).