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.
Dr Louis Allott Louis.Allott@hull.ac.uk
Lecturer in Translational Radiopharmaceutics
Eric O. Aboagye
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.
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), https://doi.org/10.3390/pharmaceutics13071078
|Journal Article Type||Article|
|Acceptance Date||Jul 9, 2021|
|Online Publication Date||Jul 14, 2021|
|Deposit Date||Jul 28, 2021|
|Publicly Available Date||Jul 29, 2021|
|Peer Reviewed||Peer Reviewed|
|Keywords||Choline kinase alpha (CHKA) inhibitor; ICL-CCIC-0019; Prodrug; PSMA; Targeted drug delivery; PIK4CB|
Publisher Licence URL
Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).
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