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
, which inhibits the growth of different tumor cells at submicromolar concentrations. Moreover,
is more potent in inhibiting CKα1 than other previous biscationic derivatives. Treatment of A549, Hela, and MDA-MB-231 cells with
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
is a promising new chemotherapeutic agent with encouraging preclinical potential.
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.
Seeking for new anticancer drugs with strong antiproliferative activity and simple molecular structure, we designed a novel series of compounds based on our previous reported pharmacophore model ...composed of five moieties. Antiproliferative assays on four tumoral cell lines and evaluation of Human Choline Kinase CKα1 enzymatic activity was performed for these compounds. Among tested molecules, those ones with biphenyl spacer showed betters enzymatic and antiproliferative activities (n-v). Docking and crystallization studies validate the hypothesis and confirm the results. The most active compound (t) induces a significant arrest of the cell cycle in G0/G1 phase that ultimately lead to apoptosis, following the mitochondrial pathway, as demonstrated for other choline kinase inhibitors. However additional assays reveal that the inhibition of choline uptake could also be involved in the antiproliferative outcome of this class of compounds.
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•C series compounds show the greatest inhibitory activity on the choline kinase (CKα1) enzyme in accordance with our previous pharmacophore model RRRPN.•These compounds also inhibit choline uptake.•Compound t induces apoptosis following mitochondrial depolarization.
Changes in gene expression profiles among individuals with inflammatory bowel diseases (IBDs) could potentially influence the responsiveness to anti-TNF treatment. The aim of this study was to ...identify genes that could serve as predictors of early response to anti-TNF therapies in pediatric IBD patients prior to the initiation of treatment.
We conducted a prospective, longitudinal, and multicenter study, enrolling 24 pediatric IBD patients aged less than 18 years who were initiating treatment with either infliximab or adalimumab. RNA-seq from blood samples was analyzed using the DESeq2 library by comparing responders and non-responders to anti-TNF drugs.
Bioinformatic analyses unveiled 102 differentially expressed genes, with 99 genes exhibiting higher expression in responders compared to non-responders prior to the initiation of anti-TNF therapy. Functional enrichment analyses highlighted defense response to Gram-negative bacteria (FDR = 2.3 ×10–7) as the most significant biological processes, and hemoglobin binding (FDR = 0.002), as the most significant molecular function. Gene Set Enrichment Analysis (GSEA) revealed notable enrichment in transcriptional misregulation in cancer (FDR = 0.016). Notably, 13 genes (CEACAM8, CEACAM6, CILP2, COL17A1, OLFM4, INHBA, LCN2, LTF, MMP8, DEFA4, PRTN3, AZU1, and ELANE) were selected for validation, and a consistent trend of increased expression in responders prior to drug administration was observed for most of these genes, with findings for 4 of them being statistically significant (CEACAM8, LCN2, LTF2, and PRTN3).
We identified 102 differentially expressed genes involved in the response to anti-TNF drugs in children with IBDs and validated CEACAM8, LCN2, LTF2, and PRTN3. Genes participating in defense response to Gram-negative bacterium, serine-type endopeptidase activity, and transcriptional misregulation in cancer are good candidates for anticipating the response to anti-TNF drugs in children with IBDs.
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•Baseline gene expression in blood associates with the response to anti-TNF drugs.•RNA-seq identified 102 genes associated with the response to anti-TNF drugs.•PRTN3, LTF, LCN, and CEACAM8 are overexpressed in responder children.•Cancer-related genes impact the response to anti-TNF drugs.•Overexpressed genes in responder children directly link to TNF processes.
Choline kinase α inhibitors represent one of the newest classes of cytotoxic drugs for cancer treatment, since aberrant choline metabolism is a characteristic shared by many human cancers.
Here, we ...present a new class of asymmetrical pyridinium/quinolinium derivatives developed and designed based on drug optimization.
Among all compounds described here, compound
, bearing a 7-chloro-4N-methyl-p-chloroaniline quinolinium moiety, exhibited the greatest inhibitory activity at the enzyme (IC
= 0.29 μM) and antiproliferative activity in cellular assays (GI
= 0.29-0.92 μM). Specifically, compound
strongly induces a cell-cycle arrest in G1 phase, but it does not significantly induce apoptosis while causing senescence in the MDA-MB-231 cell line.
We read with interest Dmitri Nepogodiev and colleagues' Correspondence (July 30, p 459) 1 supporting European research collaboration after Brexit. Research collaboratives in the UK have shown that ...multicentre studies can be run by trainees, enabling a change in the traditional paradigm of clinical research, which in turn provides benefit to both patients and investigators.
Unfortunately, the collaborators of the above mentioned article was missed out in the affiliation of the original publication. The details of them are listed below.
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