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22 pages, 1928 KiB

Open AccessArticle

Biological Evaluation of New Thienopyridinium and Thienopyrimidinium Derivatives as Human Choline Kinase Inhibitors

by Pilar María Luque-Navarro, Elena Mariotto, Marco Ballarotto, Gianluca Rubbini, Francisco José Aguilar-Troyano, Alberto Fasiolo, Archimede Torretta, Emilio Parisini, Antonio Macchiarulo, Alejandro Laso, Carmen Marco, Giampietro Viola, María Paz Carrasco-Jimenez and Luisa Carlota López-Cara

Pharmaceutics 2022, 14(4), 715; https://doi.org/10.3390/pharmaceutics14040715 - 27 Mar 2022

Cited by 2 | Viewed by 1841

Abstract

Due to its role in lipid biosynthesis, choline kinase α1 (CKα1) is an interesting target for the development of new antitumor agents. In this work, we present a series of 41 compounds designed based on the well-known and successful strategy of introducing thienopyridine [...] Read more.

Due to its role in lipid biosynthesis, choline kinase α1 (CKα1) is an interesting target for the development of new antitumor agents. In this work, we present a series of 41 compounds designed based on the well-known and successful strategy of introducing thienopyridine and pyrimidine as bioisosteres of other heterocycles in active antitumor compounds. Notwithstanding the fact that some of these compounds do not show significant enzymatic inhibition, others, in contrast, feature substantially improved enzymatic and antiproliferative inhibition values. This is also confirmed by docking analysis, whereby compounds with longer linkers and thienopyrimidine cationic head have been identified as the most compelling. Among the best compounds is Ff-35, which inhibits the growth of different tumor cells at submicromolar concentrations. Moreover, Ff-35 is more potent in inhibiting CKα1 than other previous biscationic derivatives. Treatment of A549, Hela, and MDA-MB-231 cells with Ff-35 results in their arrest at the G1 phase of the cell cycle. Furthermore, the compound induces cellular apoptosis in a concentration-dependent manner. Altogether, these findings indicate that Ff-35 is a promising new chemotherapeutic agent with encouraging preclinical potential. Full article

(This article belongs to the Special Issue Choline kinase, a Target with Broad-Spectrum Therapeutic Potential: Opportunities and Challenges)

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18 pages, 2244 KiB

Open AccessArticle

Anticancer Activity of the Choline Kinase Inhibitor PL48 Is Due to Selective Disruption of Choline Metabolism and Transport Systems in Cancer Cell Lines

by Pablo García-Molina, Alberto Sola-Leyva, Pilar M. Luque-Navarro, Alejandro Laso, Pablo Ríos-Marco, Antonio Ríos, Daniela Lanari, Archimede Torretta, Emilio Parisini, Luisa C. López-Cara, Carmen Marco and María P. Carrasco-Jiménez

Pharmaceutics 2022, 14(2), 426; https://doi.org/10.3390/pharmaceutics14020426 - 16 Feb 2022

Cited by 3 | Viewed by 3242

Abstract

A large number of different types of cancer have been shown to be associated with an abnormal metabolism of phosphatidylcholine (PC), the main component of eukaryotic cell membranes. Indeed, the overexpression of choline kinase α1 (ChoKα1), the enzyme that catalyses the bioconversion of [...] Read more.

A large number of different types of cancer have been shown to be associated with an abnormal metabolism of phosphatidylcholine (PC), the main component of eukaryotic cell membranes. Indeed, the overexpression of choline kinase α1 (ChoKα1), the enzyme that catalyses the bioconversion of choline to phosphocholine (PCho), has been found to associate with cell proliferation, oncogenic transformation and carcinogenesis. Hence, ChoKα1 has been described as a possible cancer therapeutic target. Moreover, the choline transporter CTL1 has been shown to be highly expressed in several tumour cell lines. In the present work, we evaluate the antiproliferative effect of PL48, a rationally designed inhibitor of ChoKα1, in MCF7 and HepG2 cell lines. In addition, we illustrate that the predominant mechanism of cellular choline uptake in these cells is mediated by the CTL1 choline transporter. A possible correlation between the inhibition of both choline uptake and ChoKα1 activity and cell proliferation in cancer cell lines is also highlighted. We conclude that the efficacy of this inhibitor on cell proliferation in both cell lines is closely correlated with its capability to block choline uptake and ChoKα1 activity, making both proteins potential targets in cancer therapy. Full article

(This article belongs to the Special Issue Choline kinase, a Target with Broad-Spectrum Therapeutic Potential: Opportunities and Challenges)

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21 pages, 4225 KiB

Open AccessArticle

New Compounds with Bioisosteric Replacement of Classic Choline Kinase Inhibitors Show Potent Antiplasmodial Activity

by Francisco José Aguilar-Troyano, Archimede Torretta, Gianluca Rubbini, Alberto Fasiolo, Pilar María Luque-Navarro, María Paz Carrasco-Jimenez, Guiomar Pérez-Moreno, Cristina Bosch-Navarrete, Dolores González-Pacanowska, Emilio Parisini and Luisa Carlota Lopez-Cara

Pharmaceutics 2021, 13(11), 1842; https://doi.org/10.3390/pharmaceutics13111842 - 02 Nov 2021

Cited by 1 | Viewed by 2469

Abstract

In the fight against Malaria, new strategies need to be developed to avoid resistance of the parasite to pharmaceutics and other prevention barriers. Recently, a Host Directed Therapy approach based on the suppression of the starting materials uptake from the host by the [...] Read more.

In the fight against Malaria, new strategies need to be developed to avoid resistance of the parasite to pharmaceutics and other prevention barriers. Recently, a Host Directed Therapy approach based on the suppression of the starting materials uptake from the host by the parasite has provided excellent results. In this article, we propose the synthesis of bioisosteric compounds that are capable of inhibiting Plasmodium falciparum Choline Kinase and therefore to reduce choline uptake, which is essential for the development of the parasite. Of the 41 bioisosteric compounds reported herein, none showed any influence of the linker on the antimalarial and enzyme inhibitory activity, whereas an effect of the type of cationic heads used could be observed. SARs determined that the thienopyrimidine substituted in 4 by a pyrrolidine is the best scaffold, independently of the chosen linker. The decrease in lipophilicity seems to improve the antimalarial activity but to cause an opposite effect on the inhibition of the enzyme. While potent compounds with similar good inhibitory values have been related to the proposed mechanism of action, some of them still show discrepancies and further studies are needed to determine their specific molecular target. Full article

(This article belongs to the Special Issue Choline kinase, a Target with Broad-Spectrum Therapeutic Potential: Opportunities and Challenges)

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14 pages, 2037 KiB

Open AccessArticle

Anticancer and Structure Activity Relationship of Non-Symmetrical Choline Kinase Inhibitors

by Santiago Schiaffino-Ortega, Elena Mariotto, Pilar María Luque-Navarro, María Kimatrai-Salvador, Pablo Rios-Marco, Ramon Hurtado-Guerrero, Carmen Marco, María Paz Carrasco-Jimenez, Giampietro Viola and Luisa Carlota López-Cara

Pharmaceutics 2021, 13(9), 1360; https://doi.org/10.3390/pharmaceutics13091360 - 29 Aug 2021

Cited by 3 | Viewed by 2099

Abstract

Choline kinase inhibitors are an outstanding class of cytotoxic compounds useful for the treatment of different forms of cancer since aberrant choline metabolism is a feature of neoplastic cells. Here, we present the most in-depth structure-activity relationship studies of an interesting series of [...] Read more.

Choline kinase inhibitors are an outstanding class of cytotoxic compounds useful for the treatment of different forms of cancer since aberrant choline metabolism is a feature of neoplastic cells. Here, we present the most in-depth structure-activity relationship studies of an interesting series of non-symmetric choline kinase inhibitors previously reported by our group: 3a–h and 4a–h. They are characterized by cationic heads of 3-aminophenol bound to 4-(dimethylamino)- or 4-(pyrrolidin-1-yl)pyridinium through several linkers. These derivatives were evaluated both for their inhibitory activity on the enzyme and their antiproliferative activity in a panel of six human tumor cell lines. The compounds with the N-atom connected to the linker (4a–h) show the best inhibitory results, in the manner of results supported by docking studies. On the contrary, the best antiproliferative compounds were those with the O-atom bounded to the linker (3a–h). On the other hand, as was predictable in both families, the inhibitory effect on the enzyme is better the shorter the length of the linker. However, in tumor cells, lipophilicity and choline uptake inhibition could play a decisive role. Interestingly, compounds 3c and 4f, selected for both their ability to inhibit the enzyme and good antiproliferative activity, are endowed with low toxicity in non-tumoral cells (e.g., human peripheral lymphocytes) concerning cancer cells. These compounds were also able to induce apoptosis in Jurkat leukemic cells without causing significant variations of the cell cycle. It is worth mentioning that these derivatives, besides their inhibitory effect on choline kinase, displayed a modest ability to inhibit choline uptake thus suggesting that this mechanism may also contribute to the observed cytotoxicity. Full article

(This article belongs to the Special Issue Choline kinase, a Target with Broad-Spectrum Therapeutic Potential: Opportunities and Challenges)

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18 pages, 3215 KiB

Open AccessArticle

Consideration of Metabolite Efflux in Radiolabelled Choline Kinetics

by Yunqing Li, Marianna Inglese, Suraiya Dubash, Chris Barnes, Diana Brickute, Marta Costa Braga, Ning Wang, Alice Beckley, Kathrin Heinzmann, Louis Allott, Haonan Lu, Cen Chen, Ruisi Fu, Laurence Carroll and Eric O. Aboagye

Pharmaceutics 2021, 13(8), 1246; https://doi.org/10.3390/pharmaceutics13081246 - 12 Aug 2021

Cited by 5 | Viewed by 2262

Abstract

Hypoxia is a complex microenvironmental condition known to regulate choline kinase α (CHKA) activity and choline transport through transcription factor hypoxia-inducible factor-1α (HIF-1α) and, therefore, may confound the uptake of choline radiotracer [¹⁸F]fluoromethyl-[1,2-²H₄]-choline ([¹⁸F]-D4-FCH). The [...] Read more.

Hypoxia is a complex microenvironmental condition known to regulate choline kinase α (CHKA) activity and choline transport through transcription factor hypoxia-inducible factor-1α (HIF-1α) and, therefore, may confound the uptake of choline radiotracer [¹⁸F]fluoromethyl-[1,2-²H₄]-choline ([¹⁸F]-D4-FCH). The aim of this study was to investigate how hypoxia affects the choline radiotracer dynamics. Three underlying mechanisms by which hypoxia could potentially alter the uptake of the choline radiotracer, [¹⁸F]-D4-FCH, were investigated: ¹⁸F-D4-FCH import, CHKA phosphorylation activity, and the efflux of [¹⁸F]-D4-FCH and its phosphorylated product [¹⁸F]-D4-FCHP. The effects of hypoxia on [¹⁸F]-D4-FCH uptake were studied in CHKA-overexpressing cell lines of prostate cancer, PC-3, and breast cancer MDA-MB-231 cells. The mechanisms of radiotracer efflux were assessed by the cell uptake and immunofluorescence in vitro and examined in vivo (n = 24). The mathematical modelling methodology was further developed to verify the efflux hypothesis using [¹⁸F]-D4-FCH dynamic PET scans from non-small cell lung cancer (NSCLC) patients (n = 17). We report a novel finding involving the export of phosphorylated [¹⁸F]-D4-FCH and [¹⁸F]-D4-FCHP via HIF-1α-responsive efflux transporters, including ABCB4, when the HIF-1α level is augmented. This is supported by a graphical analysis of human data with a compartmental model (M2T6k + k₅) that accounts for the efflux. Hypoxia/HIF-1α increases the efflux of phosphorylated radiolabelled choline species, thus supporting the consideration of efflux in the modelling of radiotracer dynamics. Full article

(This article belongs to the Special Issue Choline kinase, a Target with Broad-Spectrum Therapeutic Potential: Opportunities and Challenges)

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17 pages, 4187 KiB

Open AccessArticle

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

by Ning Wang, Diana Brickute, Marta Braga, Chris Barnes, Haonan Lu, Louis Allott and Eric O. Aboagye

Pharmaceutics 2021, 13(7), 1078; https://doi.org/10.3390/pharmaceutics13071078 - 14 Jul 2021

Cited by 2 | Viewed by 3356

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Choline kinase, a Target with Broad-Spectrum Therapeutic Potential: Opportunities and Challenges)

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Review

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15 pages, 1389 KiB

Open AccessReview

ChoK-Full of Potential: Choline Kinase in B Cell and T Cell Malignancies

by Samantha Gokhale and Ping Xie

Pharmaceutics 2021, 13(6), 911; https://doi.org/10.3390/pharmaceutics13060911 - 20 Jun 2021

Cited by 12 | Viewed by 2712

Abstract

Aberrant choline metabolism, characterized by an increase in total choline-containing compounds, phosphocholine and phosphatidylcholine (PC), is a metabolic hallmark of carcinogenesis and tumor progression. This aberration arises from alterations in metabolic enzymes that control PC biosynthesis and catabolism. Among these enzymes, choline kinase [...] Read more.

Aberrant choline metabolism, characterized by an increase in total choline-containing compounds, phosphocholine and phosphatidylcholine (PC), is a metabolic hallmark of carcinogenesis and tumor progression. This aberration arises from alterations in metabolic enzymes that control PC biosynthesis and catabolism. Among these enzymes, choline kinase α (CHKα) exhibits the most frequent alterations and is commonly overexpressed in human cancers. CHKα catalyzes the phosphorylation of choline to generate phosphocholine, the first step in de novo PC biosynthesis. CHKα overexpression is associated with the malignant phenotype, metastatic capability and drug resistance in human cancers, and thus has been recognized as a robust biomarker and therapeutic target of cancer. Of clinical importance, increased choline metabolism and CHKα activity can be detected by non-invasive magnetic resonance spectroscopy (MRS) or positron emission tomography/computed tomography (PET/CT) imaging with radiolabeled choline analogs for diagnosis and treatment monitoring of cancer patients. Both choline-based MRS and PET/CT imaging have also been clinically applied for lymphoid malignancies, including non-Hodgkin lymphoma, multiple myeloma and central nervous system lymphoma. However, information on how choline kinase is dysregulated in lymphoid malignancies is very limited and has just begun to be unraveled. In this review, we provide an overview of the current understanding of choline kinase in B cell and T cell malignancies with the goal of promoting future investigation in this area. Full article

(This article belongs to the Special Issue Choline kinase, a Target with Broad-Spectrum Therapeutic Potential: Opportunities and Challenges)

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28 pages, 3588 KiB

Open AccessReview

Choline Kinase: An Unexpected Journey for a Precision Medicine Strategy in Human Diseases

by Juan Carlos Lacal, Tahl Zimmerman and Joaquín M. Campos

Pharmaceutics 2021, 13(6), 788; https://doi.org/10.3390/pharmaceutics13060788 - 25 May 2021

Cited by 12 | Viewed by 3695

Abstract

Choline kinase (ChoK) is a cytosolic enzyme that catalyzes the phosphorylation of choline to form phosphorylcholine (PCho) in the presence of ATP and magnesium. ChoK is required for the synthesis of key membrane phospholipids and is involved in malignant transformation in [...] Read more.

Choline kinase (ChoK) is a cytosolic enzyme that catalyzes the phosphorylation of choline to form phosphorylcholine (PCho) in the presence of ATP and magnesium. ChoK is required for the synthesis of key membrane phospholipids and is involved in malignant transformation in a large variety of human tumours. Active compounds against ChoK have been identified and proposed as antitumor agents. The ChoK inhibitory and antiproliferative activities of symmetrical bispyridinium and bisquinolinium compounds have been defined using quantitative structure–activity relationships (QSARs) and structural parameters. The design strategy followed in the development of the most active molecules is presented. The selective anticancer activity of these structures is also described. One promising anticancer compound has even entered clinical trials. Recently, ChoKα inhibitors have also been proposed as a novel therapeutic approach against parasites, rheumatoid arthritis, inflammatory processes, and pathogenic bacteria. The evidence for ChoKα as a novel drug target for approaches in precision medicine is discussed. Full article

(This article belongs to the Special Issue Choline kinase, a Target with Broad-Spectrum Therapeutic Potential: Opportunities and Challenges)

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