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Journal of Enzyme Inhibition and... Dec 2024A series of novel benzimidazole derivatives were designed and synthesised based on the structures of reported oral available ALK inhibitor and HDAC inhibitor,...
Discovery of novel anaplastic lymphoma kinase (ALK) and histone deacetylase (HDAC) dual inhibitors exhibiting antiproliferative activity against non-small cell lung cancer.
A series of novel benzimidazole derivatives were designed and synthesised based on the structures of reported oral available ALK inhibitor and HDAC inhibitor, pracinostat. In enzymatic assays, compound , containing a 2-acyliminobenzimidazole moiety and hydroxamic acid side chain, could inhibit both ALK and HDAC6 (IC = 16 nM and 1.03 µM, respectively). Compound also inhibited various ALK mutants known to be involved in crizotinib resistance, including mutant L1196M (IC, 4.9 nM). Moreover, inhibited the proliferation of several cancer cell lines, including ALK-addicted H2228 cells. To evaluate its potential for treating cancers , was used in a human A549 xenograft model with BALB/c nude mice. At 20 mg/kg, inhibited tumour growth by 85% yet had a negligible effect on mean body weight. These results suggest a attracting route for the further research and optimisation of dual ALK/HDAC inhibitors.
Topics: Mice; Animals; Humans; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Histone Deacetylase Inhibitors; Mice, Nude; Lung Neoplasms; Cell Proliferation; Protein Kinase Inhibitors; Antineoplastic Agents; Cell Line, Tumor
PubMed: 38465731
DOI: 10.1080/14756366.2024.2318645 -
Journal of Pharmaceutical Analysis Oct 2023Divisions at the periphery and midzone of mitochondria are two fission signatures that determine the fate of mitochondria and cells. Pharmacological induction of...
Divisions at the periphery and midzone of mitochondria are two fission signatures that determine the fate of mitochondria and cells. Pharmacological induction of excessively asymmetric mitofission-associated cell death (MFAD) by switching the scission position from the mitochondrial midzone to the periphery represents a promising strategy for anticancer therapy. By screening a series of pan-inhibitors, we identified pracinostat, a pan-histone deacetylase (HDAC) inhibitor, as a novel MFAD inducer, that exhibited a significant anticancer effect on colorectal cancer (CRC) in vivo and in vitro. Pracinostat increased the expression of cyclin-dependent kinase 5 (CDK5) and induced its acetylation at residue lysine 33, accelerating the formation of complex CDK5/CDK5 regulatory subunit 1 and dynamin-related protein 1 (Drp1)-mediated mitochondrial peripheral fission. CRC cells with high level of CDK5 (CDK5-high) displayed midzone mitochondrial division that was associated with oncogenic phenotype, but treatment with pracinostat led to a lethal increase in the already-elevated level of CDK5 in the CRC cells. Mechanistically, pracinostat switched the scission position from the mitochondrial midzone to the periphery by improving the binding of Drp1 from mitochondrial fission factor (MFF) to mitochondrial fission 1 protein (FIS1). Thus, our results revealed the anticancer mechanism of HDACi pracinostat in CRC via activating CDK5-Drp1 signaling to cause selective MFAD of those CDK5-high tumor cells, which implicates a new paradigm to develop potential therapeutic strategies for CRC treatment.
PubMed: 38024857
DOI: 10.1016/j.jpha.2023.06.005 -
Brain Sciences Sep 2023The relationship between N6-methyladenosine (m6A) regulators and anoikis and their effects on low-grade glioma (LGG) is not clear yet. The TCGA-LGG cohort, mRNAseq 325...
The relationship between N6-methyladenosine (m6A) regulators and anoikis and their effects on low-grade glioma (LGG) is not clear yet. The TCGA-LGG cohort, mRNAseq 325 dataset, and GSE16011 validation set were separately obtained via the Cancer Genome Atlas (TCGA), Chinese Glioma Genome Altas (CGGA), and Gene Expression Omnibus (GEO) databases. In total, 27 m6A-related genes (m6A-RGs) and 508 anoikis-related genes (ANRGs) were extracted from published articles individually. First, differentially expressed genes (DEGs) between LGG and normal samples were sifted out by differential expression analysis. DEGs were respectively intersected with m6A-RGs and ANRGs to acquire differentially expressed m6A-RGs (DE-m6A-RGs) and differentially expressed ANRGs (DE-ANRGs). A correlation analysis of DE-m6A-RGs and DE-ANRGs was performed to obtain DE-m6A-ANRGs. Next, univariate Cox and least absolute shrinkage and selection operator (LASSO) were performed on DE-m6A-ANRGs to sift out risk model genes, and a risk score was gained according to them. Then, gene set enrichment analysis (GSEA) was implemented based on risk model genes. After that, we constructed an independent prognostic model and performed immune infiltration analysis and drug sensitivity analysis. Finally, an mRNA-miRNA-lncRNA regulatory network was constructed. There were 6901 DEGs between LGG and normal samples. Six DE-m6A-RGs and 214 DE-ANRGs were gained through intersecting DEGs with m6A-RGs and ANRGs, respectively. A total of 149 DE-m6A-ANRGs were derived after correlation analysis. Four genes, namely ANXA5, KIF18A, BRCA1, and HOXA10, composed the risk model, and they were involved in apoptosis, fatty acid metabolism, and glycolysis. The age and risk scores were finally sifted out to construct an independent prognostic model. Activated CD4 T cells, gamma delta T cells, and natural killer T cells had the largest positive correlations with risk model genes, while activated B cells were significantly negatively correlated with KIF18A and BRCA1. AT.9283, EXEL.2280, Gilteritinib, and Pracinostat had the largest correlation (absolute value) with a risk score. Four risk model genes (mRNAs), 12 miRNAs, and 21 lncRNAs formed an mRNA-miRNA-lncRNA network, containing HOXA10-hsa-miR-129-5p-LINC00689 and KIF18A-hsa-miR-221-3p-DANCR. Through bioinformatics, we constructed a prognostic model of m6A-associated anoikis genes in LGG, providing new ideas for research related to the prognosis and treatment of LGG.
PubMed: 37759912
DOI: 10.3390/brainsci13091311