Crystal Structure of the Apo and the ADP-Bound Form of Choline Kinase from Plasmodium falciparum

Torretta, Archimede; Cara, Carlota Lopez; Parisini, Emilio

doi:10.3390/cryst10070613

Cited by 4 publications

(6 citation statements)

References 39 publications

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“…Kinase promiscuity can lower compound activity towards the desired target and induce adverse effects, both of which are undesirable characteristics for cancer therapeutics; however, it is noteworthy that the structure (CK146) presented here may have potential to be further modified into anti-parasite or antiviral drugs with a dual target-hitting PIK4CB and CHKA alike. This may warrant further investigation by researchers in the field, perhaps further supported by in silico docking studies against P. falciparum CHKA (pdb code: 6YXS) [ 51 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“… 45 Recently, structures of P. falciparum choline kinase ( Pf ChoK) and hexokinase have also been reported. 11 , 13 To our knowledge, no Plasmodium PIK structures have been elucidated to date.…”

Section: Key Structural Features Of Kinasesmentioning

confidence: 99%

“…High-resolution structures of at least 11 different Plasmodium protein kinases have been solved ( Pb CDPK1 (3Q5I), Pf CDPK2 (4MVF), Pf CDPK4 (4QOX, 4RGJ), Pf CK2 (5XVU), Pf CLK1 (3LLT), Pf MAPK2 (3NIE), Pb MAPK2 (3N9X), Pf PK5 (e.g., 1OB3), Pf PK7 (e.g., 2PMN), Pf PKG (5DYK), and Pv PKG (e.g., 5DZC). Recently, structures of P. falciparum choline kinase ( Pf ChoK) and hexokinase have also been reported. , To our knowledge, no Plasmodium PIK structures have been elucidated to date.…”

Section: Key Structural Features Of Kinasesmentioning

confidence: 99%

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Plasmodium Kinases as Potential Drug Targets for Malaria: Challenges and Opportunities

et al. 2021

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Protein and phosphoinositide kinases have been successfully exploited as drug targets in various disease areas, principally in oncology. In malaria, several protein kinases are under investigation as potential drug targets, and an inhibitor of Plasmodium phosphatidylinositol 4-kinase type III beta (PI4KIIIβ) is currently in phase 2 clinical studies. In this Perspective, we review the potential of kinases as drug targets for the treatment of malaria. Kinases are known to be readily druggable, and many are essential for parasite survival. A key challenge in the design of Plasmodium kinase inhibitors is obtaining selectivity over the corresponding human orthologue(s) and other human kinases due to the highly conserved nature of the shared ATP binding site. Notwithstanding this, there are some notable differences between the Plasmodium and human kinome that may be exploitable. There is also the potential for designed polypharmacology, where several Plasmodium kinases are inhibited by the same drug. Prior to starting the drug discovery process, it is important to carefully assess potential kinase targets to ensure that the inhibition of the desired kinase will kill the parasites in the required life-cycle stages with a sufficiently fast rate of kill. Here, we highlight key target attributes and experimental approaches to consider and summarize the progress that has been made targeting Plasmodium PI4KIIIβ, cGMP-dependent protein kinase, and cyclin-dependent-like kinase 3.

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“…Some promising inhibitors have been discovered by the repurposing of hChoK inhibitors [88,139]. This repurposing strategy is effective because the primary structure of the active site of pf-ChoK (Figure 4), as well as the tertiary structure (Figure 5), are highly conserved with respect to hChoK [140]. For example, hChoK inhibitors MN58b and RSM-932A inhibit pfChoK in the micromolar range [88].…”

Section: Plasmodium Falciparum and Chokmentioning

confidence: 99%

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

Lacal

Zimmerman²,

Campos

2021

Pharmaceutics

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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.

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Crystal Structure of the Apo and the ADP-Bound Form of Choline Kinase from Plasmodium falciparum

Cited by 4 publications

References 39 publications

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

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

Plasmodium Kinases as Potential Drug Targets for Malaria: Challenges and Opportunities

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

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