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Novel non-congeneric derivatives of the choline kinase alpha inhibitor ICL-CCIC-0019

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Title: Novel non-congeneric derivatives of the choline kinase alpha inhibitor ICL-CCIC-0019
Authors: Aboagye, E
Wang, N
Brickute, D
Braga, M
Barnes, C
Lu, H
Allott, L
Item Type: Journal Article
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.
Issue Date: 14-Jul-2021
Date of Acceptance: 9-Jul-2021
URI: http://hdl.handle.net/10044/1/90857
DOI: 10.3390/pharmaceutics13071078
ISSN: 1999-4923
Publisher: MDPI AG
Start Page: 1
End Page: 17
Journal / Book Title: Pharmaceutics
Volume: 13
Issue: 7
Copyright Statement: © 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/).
Sponsor/Funder: Cancer Research UK
Funder's Grant Number: 28680
Keywords: Science & Technology
Life Sciences & Biomedicine
Pharmacology & Pharmacy
choline kinase alpha (CHKA) inhibitor
ICL-CCIC-0019
prodrug
PSMA
targeted drug delivery
PIK4CB
ANTIPROLIFERATIVE ACTIVITY
LIPID-METABOLISM
STRATEGIES
MECHANISM
RSM-932A
ISOFORMS
DESIGN
TARGET
CELLS
1115 Pharmacology and Pharmaceutical Sciences
Publication Status: Published
Online Publication Date: 2021-07-14
Appears in Collections:Department of Surgery and Cancer



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