Novel non-congeneric derivatives of the choline kinase alpha inhibitor ICL-CCIC-0019
File(s)
Published version
Author(s)
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.
Date Issued
2021-07-14
Date Acceptance
2021-07-09
Citation
Pharmaceutics, 2021, 13 (7), pp.1-17
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/).
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/).
License URL
Sponsor
Cancer Research UK
Identifier
https://www.mdpi.com/1999-4923/13/7/1078
Grant Number
28680
Subjects
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
Date Publish Online
2021-07-14