Novel Non-Congeneric Derivatives of the Choline Kinase Alpha Inhibitor ICL-CCIC-0019

Abstract

Choline kinase alpha (CHKA) is a promising target for the development of cancer therapeutics. We have previously reported ICL-CCIC-0019, a potent CHKA inhibitor with high cellular activity but with some unfavorable pharmacological properties. In this work, we present an active analogue of ICL-CCIC-0019 bearing a piperazine handle (CK146) to facilitate further structural elaboration of the pharmacophore and thus improve the biological profile. Two different strategies were evaluated in this study: (1) a prodrug approach whereby selective CHKA inhibition could be achieved through modulating the activity of CK146, via the incorporation of an ε-(Ac) Lys motif, cleavable by elevated levels of histone deacetylase (HDAC) and cathepsin L (CTSL) in tumour cells; (2) a prostate-specific membrane antigen (PSMA) receptor targeted delivery strategy. Prodrug (CK145) and PSMA-targeted (CK147) derivatives were successfully synthesized and evaluated in vitro. While the exploitation of CK146 in those two strategies did not deliver the expected results, important and informative structure-activity relationships were observed and have been reported.

MALAT1 as a Regulator of the Androgen-Dependent Choline Kinase A Gene in the Metabolic Rewiring of Prostate Cancer

“…Consistently, shRNA-mediated in vivo depletion of CHKA decreases the growth of prostate tumor xenografts [ 5 ]. Very efficient CHKA inhibitors have been developed and considered in clinical trials, however, they have manifested elevated toxicity, as reported in [ 7 , 15 , 16 , 17 ]. Hence, alternative strategies should be considered.…”