Novel Non-Congeneric Derivatives of the Choline Kinase Alpha Inhibitor ICL-CCIC-0019.
ICL-CCIC-0019
PIK4CB
PSMA
choline kinase alpha (CHKA) inhibitor
prodrug
targeted drug delivery
Journal
Pharmaceutics
ISSN: 1999-4923
Titre abrégé: Pharmaceutics
Pays: Switzerland
ID NLM: 101534003
Informations de publication
Date de publication:
14 Jul 2021
14 Jul 2021
Historique:
received:
22
06
2021
revised:
06
07
2021
accepted:
09
07
2021
entrez:
10
8
2021
pubmed:
11
8
2021
medline:
11
8
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34371769
pii: pharmaceutics13071078
doi: 10.3390/pharmaceutics13071078
pmc: PMC8309005
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : China Sponsorship Council
ID : N/A
Organisme : Medical Research Council
ID : MR/M015858/1
Pays : United Kingdom
Organisme : NIHR Imperial Biomedical Research Centre
ID : WSCC_P62585
Organisme : Imperial Experimental Cancer Medicine Centre
ID : C1312/A25149
Organisme : National Cancer Imaging Translational Accelerator
ID : C2536/A28680
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