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Article

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

1
Comprehensive Cancer Imaging Centre, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK
2
Positron Emission Tomography Research Centre, Faculty of Health Sciences, University of Hull, Kingston upon Hull HU6 7RX, UK
*
Authors to whom correspondence should be addressed.
Academic Editor: Luisa Carlota Lopez-Cara
Pharmaceutics 2021, 13(7), 1078; https://doi.org/10.3390/pharmaceutics13071078
Received: 22 June 2021 / Revised: 6 July 2021 / Accepted: 9 July 2021 / Published: 14 July 2021
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. View Full-Text
Keywords: choline kinase alpha (CHKA) inhibitor; ICL-CCIC-0019; prodrug; PSMA; targeted drug delivery; PIK4CB choline kinase alpha (CHKA) inhibitor; ICL-CCIC-0019; prodrug; PSMA; targeted drug delivery; PIK4CB
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MDPI and ACS Style

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

AMA Style

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

Chicago/Turabian Style

Wang, Ning, Diana Brickute, Marta Braga, Chris Barnes, Haonan Lu, Louis Allott, and Eric O. Aboagye 2021. "Novel Non-Congeneric Derivatives of the Choline Kinase Alpha Inhibitor ICL-CCIC-0019" Pharmaceutics 13, no. 7: 1078. https://doi.org/10.3390/pharmaceutics13071078

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