Identification of Unprecedented ATP-competitive Choline Kinase Inhibitors

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.

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

Pharmaceutics ◽

10.3390/pharmaceutics13091360 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1360

Author(s):

Santiago Schiaffino-Ortega ◽

Elena Mariotto ◽

Pilar María Luque-Navarro ◽

María Kimatrai-Salvador ◽

Pablo Rios-Marco ◽

...

Keyword(s):

Antiproliferative Activity ◽

Kinase Inhibitors ◽

Human Tumor ◽

Structure Activity Relationship ◽

Inhibitory Effect ◽

Activity Relationship ◽

Choline Kinase ◽

Choline Uptake ◽

Uptake Inhibition ◽

Structure Activity

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.

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Choline kinase inhibitors EB-3D and EB-3P interferes with lipid homeostasis in HepG2 cells

Scientific Reports ◽

10.1038/s41598-019-40885-z ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 7

Author(s):

Alberto Sola-Leyva ◽

Luisa C. López-Cara ◽

Pablo Ríos-Marco ◽

Antonio Ríos ◽

Carmen Marco ◽

...

Keyword(s):

Hepg2 Cells ◽

Kinase Inhibitors ◽

Lipid Homeostasis ◽

Choline Kinase

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Identification and validation of novel and more effective choline kinase inhibitors against Streptococcus pneumoniae

Scientific Reports ◽

10.1038/s41598-020-72165-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Tahl Zimmerman ◽

Valerie Chasten ◽

Juan Carlos Lacal ◽

Salam A. Ibrahim

Keyword(s):

Streptococcus Pneumoniae ◽

Drug Target ◽

Kinase Inhibitors ◽

Teichoic Acid ◽

Cellular Level ◽

Choline Kinase ◽

Potential Therapeutic Target ◽

Enzymatic Assays ◽

Induced Autolysis ◽

Promising Avenue

Abstract Streptococcus pneumoniae choline kinase (sChoK) has previously been proposed as a drug target, yet the effectiveness of the first and only known inhibitor of sChoK, HC-3, is in the millimolar range. The aim of this study was thus to further validate sChoK as a potential therapeutic target by discovering more powerful sChoK inhibitors. LDH/PK and colorimetric enzymatic assays revealed two promising sChoK inhibitor leads RSM-932A and MN58b that were discovered with IC50 of 0.5 and 150 μM, respectively, and were shown to be 2–4 magnitudes more potent than the previously discovered inhibitor HC-3. Culture assays showed that the minimum inhibitory concentration (MIC) of RSM-932A and MN58b for S. pneumoniae was 0.4 μM and 10 μM, respectively, and the minimum lethal concentration (MLC) was 1.6 μM and 20 μM, respectively. Western blot monitoring of teichoic acid production revealed differential patterns in response to each inhibitor. In addition, both inhibitors possessed a bacteriostatic mechanism of action, and neither interfered with the autolytic effects of vancomycin. Cells treated with MN58b but not RSM-932A were more sensitive to a phosphate induced autolysis with respect to the untreated cells. SEM studies revealed that MN58b distorted the cell wall, a result consistent with the apparent teichoic acid changes. Two novel and more highly potent putative inhibitors of sChoK, MN58b and RSM-932A, were characterized in this study. However, the effects of sChoK inhibitors can vary at the cellular level. sChoK inhibition is a promising avenue to follow in the development of therapeutics for treatment of S. pneumoniae.

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ChoK-ing the Pathogenic Bacteria: Potential of Human Choline Kinase Inhibitors as Antimicrobial Agents

BioMed Research International ◽

10.1155/2020/1823485 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14

Author(s):

Moad Khalifa ◽

Ling Ling Few ◽

Wei Cun See Too

Keyword(s):

Cell Wall ◽

Targeted Delivery ◽

Pathogenic Bacteria ◽

Antimicrobial Agents ◽

Kinase Inhibitors ◽

Amino Acid Sequences ◽

Choline Kinase ◽

Anticancer Properties ◽

Wide Range ◽

Catalytic Sites

Novel antimicrobial agents are crucial to combat antibiotic resistance in pathogenic bacteria. Choline kinase (ChoK) in bacteria catalyzes the synthesis of phosphorylcholine, which is subsequently incorporated into the cell wall or outer membrane. In certain species of bacteria, phosphorylcholine is also used to synthesize membrane phosphatidylcholine. Numerous human ChoK inhibitors (ChoKIs) have been synthesized and tested for anticancer properties. Inhibition of S. pneumoniae ChoK by human ChoKIs showed a promising effect by distorting the cell wall and retarded the growth of this pathogen. Comparison of amino acid sequences at the catalytic sites of putative choline kinases from pathogenic bacteria and human enzymes revealed striking sequence conservation that supports the potential application of currently available ChoKIs for inhibiting bacterial enzymes. We also propose the combined use of ChoKIs and nanoparticles for targeted delivery to the pathogen while shielding the human host from any possible side effects of the inhibitors. More research should focus on the verification of putative bacterial ChoK activities and the characterization of ChoKIs with active enzymes. In conclusion, the presence of ChoK in a wide range of pathogenic bacteria and the distinct function of this enzyme has made it an attractive drug target. This review highlighted the possibility of “choking” bacterial ChoKs by using human ChoKIs.

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