Towards a model for the inhibition of choline kinase by a new type of inhibitor

Conejo‐García, Ana; Entrena, Antonio; Campos, Joaquı́n M.; Sánchez‐Martín, Rosario M.; Gallo, Miguel Á.; Espinosa, Antonio

doi:10.1016/j.ejmech.2004.09.016

Cited by 8 publications

(6 citation statements)

References 17 publications

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“…HC-3 has been used as a template for the design of new inhibitors, and the most potent inhibitors reported so far also contain 2-fold symmetrical, antiparallel structures like HC-3, and each possesses two quaternary ammonium rings connected by a hydrophobic spacer (20, 40). Quantitative structure-activity relationship analyses of HC-3 analogues have shown that the inhibitory potency of ChoK correlates well with both the charge on the ring nitrogen and the size of the central hydrophobic spacer (25–27, 40). These findings suggest that the inhibitor-binding site of ChoK is highly specific for predominantly hydrophobic molecules carrying positively charged nitrogens.…”

Section: Discussionmentioning

confidence: 99%

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Crystal Structures of Human Choline Kinase Isoforms in Complex with Hemicholinium-3

Hong

Allali-Hassani

Tempel

et al. 2010

Journal of Biological Chemistry

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Human choline kinase (ChoK) catalyzes the first reaction in phosphatidylcholine biosynthesis and exists as ChoKα (α1 and α2) and ChoKβ isoforms. Recent studies suggest that ChoK is implicated in tumorigenesis and emerging as an attractive target for anticancer chemotherapy. To extend our understanding of the molecular mechanism of ChoK inhibition, we have determined the high resolution x-ray structures of the ChoKα1 and ChoKβ isoforms in complex with hemicholinium-3 (HC-3), a known inhibitor of ChoK. In both structures, HC-3 bound at the conserved hydrophobic groove on the C-terminal lobe. One of the HC-3 oxazinium rings complexed with ChoKα1 occupied the choline-binding pocket, providing a structural explanation for its inhibitory action. Interestingly, the HC-3 molecule co-crystallized with ChoKβ was phosphorylated in the choline binding site. This phosphorylation, albeit occurring at a very slow rate, was confirmed experimentally by mass spectroscopy and radioactive assays. Detailed kinetic studies revealed that HC-3 is a much more potent inhibitor for ChoKα isoforms (α1 and α2) compared with ChoKβ. Mutational studies based on the structures of both inhibitor-bound ChoK complexes demonstrated that Leu-401 of ChoKα2 (equivalent to Leu-419 of ChoKα1), or the corresponding residue Phe-352 of ChoKβ, which is one of the hydrophobic residues neighboring the active site, influences the plasticity of the HC-3-binding groove, thereby playing a key role in HC-3 sensitivity and phosphorylation.

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Section: Discussionmentioning

confidence: 99%

“…In an effort to develop new anti-cancer therapies, numerous compounds have been synthesized and tested as ChoK inhibitors (20, 25–27). Most of these compounds are derivatives of hemicholinium-3 (HC-3), a known competitive inhibitor of ChoK with a structural homology to choline (Fig.…”

Section: Introductionmentioning

confidence: 99%

Crystal Structures of Human Choline Kinase Isoforms in Complex with Hemicholinium-3

Hong

Allali-Hassani

Tempel

et al. 2010

Journal of Biological Chemistry

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“…As already mentioned, the synthesis of several derivatives was first based on structural modifications of HC-3 that led to biscationic, triscationic and macrocyclic compounds, such as cyclophanes and bicyclophanes ( Figure 1). [45][46][47][48][49][50][51][52][53] All these molecules are symmetrical with pyridinium or quinolinium moieties connected through an aromatic linker. As demonstrated by preclinical candidate TCD-717, this approach is successful and justifies its use in the design of new hChoK inhibitors.…”

Section: In Drug Designmentioning

confidence: 99%

Recent advances in the design of choline kinase α inhibitors and the molecular basis of their inhibition

Rubio‐Ruíz

Serrán-Aguilera

Hurtado‐Guerrero

et al. 2020

Medicinal Research Reviews

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Up-regulated choline metabolism, characterized by an increase in phosphocholine (PCho), is a hallmark of oncogenesis and tumor progression. Choline kinase (ChoK), the enzyme responsible for PCho synthesis, has consequently become of a promising drug target for cancer therapy and as such a significant number of ChoK inhibitors have been developed over the last few decades. More recently, due to the role of this enzyme in other pathologies, ChoK inhibitors have also been used in new therapeutic approaches against malaria and rheumatoid arthritis. Here, we review research results in the field of ChoKα inhibitors from their synthesis to the molecular basis of their binding mode. Strategies for the development of inhibitors and their selectivity on ChoKα over ChoKβ, the plasticity of the choline-binding site, the discovery of new exploitable binding sites, and the allosteric properties of this enzyme are highlighted. The outcomes summarized in this review will be a useful guide to develop new multi-functional potent drugs for the treatment of various human diseases.

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“…16 We have proposed a model for the inhibition of ChoK by using cyclophanes 4-7. 17 With the aim of obtaining new structure-activity relationships and studying in depth the structural parameters that define the ChoK inhibitory and antiproliferative activities, the synthesis of a new set of compounds is proposed based on changing the pyridinium for quinolinium moieties of the biscationic acyclic compounds.…”

Section: Introductionmentioning

confidence: 99%

Symmetrical Bis-Quinolinium Compounds: New Human Choline Kinase Inhibitors with Antiproliferative Activity against the HT-29 Cell Line

et al. 2005

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Studies have been aimed at the establishment of structure-activity relationships that define choline kinase inhibitory and antiproliferative activities of 40 bisquinolinium compounds. These derivatives have electron-releasing groups at position 4 of the quinolinium ring. It is found that the enzymatic inhibition is closely related to the size of the linker, the 3,3'-biphenyl moiety being the most suitable. On the other hand, the antiproliferative activity against the HT-29 cancer cell line is less influenced by the linker type and by substituent R(4). The corresponding QSAR equation was obtained for the whole set of compounds for the antiproliferative activity, the electronic parameter sigma(R) of R(4), the molar refractivity of R(8), and the lipophilic parameters clog P and pi(linker). The most potent antiproliferative agent so far described is 40 for which an IC(50) = 0.45 microM was predicted by the QSAR equation, while its experimental value is IC(50) = 0.20 microM.

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Towards a model for the inhibition of choline kinase by a new type of inhibitor

Cited by 8 publications

References 17 publications

Crystal Structures of Human Choline Kinase Isoforms in Complex with Hemicholinium-3

Crystal Structures of Human Choline Kinase Isoforms in Complex with Hemicholinium-3

Recent advances in the design of choline kinase α inhibitors and the molecular basis of their inhibition

Symmetrical Bis-Quinolinium Compounds: New Human Choline Kinase Inhibitors with Antiproliferative Activity against the HT-29 Cell Line

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