Choline kinase inhibition and docking studies of a series of 6-(benzylthio)-9H-purin-9-yl-pyridinium derivatives

Rubio‐Ruíz, Belén; Ríos-Marco, Pablo; Carrasco-Jiménez, María P.; Espinosa, Antonio; Hurtado‐Guerrero, R.; Marco, Carmen; Conejo‐García, Ana; Entrena, Antonio

doi:10.1007/s00044-017-1979-6

Cited by 2 publications

(3 citation statements)

References 22 publications

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“…In fact, compound 6 ( Figure 9), which possesses a benzene moiety as a spacer, is the most potent inhibitor in the series against ChoKα1 (IC50 = 0.4 μM ± 0.03). 75 A similar approach was pursued by Trousil et al that used alkyl linkers (C8 and C12) to bridge both the Cho and ATP-mimicking groups. 61 Benzimidazole, adenine and purine were explored while keeping 4-(dimethylamino) as the cationic moiety.…”

Section: Non-symmetric Pyridinium Derivativesmentioning

confidence: 99%

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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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Section: Non-symmetric Pyridinium Derivativesmentioning

confidence: 99%

“…However, the activity was also favored by short linkers, contrary to that previously observed for adenine counterparts. In fact, compound 6 (Figure 9), which possesses a benzene moiety as a spacer, is the most potent inhibitor in the series against hChoKα1 (IC 50 = 0.4 μM ± 0.03) 77 …”

Section: Harnessing the Potential Of Crystallographic Studies For Thementioning

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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“…In recent years, the x-ray crystal structure of CHKA, together with computational in silico techniques have boosted the development of CHKA inhibitors (the crystal structure of human CHKA, pdb code: 2CKO) [ 18 , 20 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. A series of symmetrical N , N -dimethylaminopyridine (DMAP) derivatives bearing alkyl linkers of varying lengths were designed by Trousil et al as CHKA inhibitors ( Figure 1 ), where DMAP mimicked cationic choline moieties [ 26 ]; from this study, ICL-CCIC-0019 was selected for further biological evaluations and displayed great potential in preclinical studies [ 27 ].…”

Section: Introductionmentioning

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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Choline kinase inhibition and docking studies of a series of 6-(benzylthio)-9H-purin-9-yl-pyridinium derivatives

Cited by 2 publications

References 22 publications

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

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

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

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