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

Wang, Ning; Brickute, Diana; Braga, Marta; Barnes, Chris; Lu, Haonan; Allott, Louis; Aboagye, Eric O.

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.

Citation

Wang, N., Brickute, D., Braga, M., Barnes, C., Lu, H., Allott, L., & Aboagye, E. O. (2021). Novel Non-Congeneric Derivatives of the Choline Kinase Alpha Inhibitor ICL-CCIC-0019. Pharmaceutics, 13(7), Article 1078. https://doi.org/10.3390/pharmaceutics13071078

• Journal Article Type: Article
• Acceptance Date: Jul 9, 2021
• Online Publication Date: Jul 14, 2021
• Publication Date: 2021-07
• Deposit Date: Jul 28, 2021
• Publicly Available Date: Jul 29, 2021
• Journal: Pharmaceutics
• Print ISSN: 1999-4923
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 7
• Article Number: 1078
• DOI: https://doi.org/10.3390/pharmaceutics13071078
• Keywords: Choline kinase alpha (CHKA) inhibitor; ICL-CCIC-0019; Prodrug; PSMA; Targeted drug delivery; PIK4CB
• Public URL: https://hull-repository.worktribe.com/output/3804357