Search Results (3)

Epigenetic readout of the combinatorial posttranslational modification comprised of trimethyllysine and asymmetric dimethylarginine (H3K4me3R8me2a) takes place via biomolecular recognition of tandem Tudor-domain-containing protein Spindlin1. Through comparative thermodynamic data and molecular dynamics simulations, we sought to explore the binding scope of asymmetric dimethylarginine mimics by Spindlin1. Herein, we provide evidence that the biomolecular recognition of H3K4me2R8me2a is not significantly affected when R8me2a is replaced by dimethylarginine analogues, implying that the binding of K4me3 provides the major binding contribution. High-energy water molecules inside both aromatic cages of the ligand binding sites contribute to the reader–histone association upon displacement by histone peptide, with the K4me3 hydration site being lower in free energy due to a flip of Trp151. Full article

Nasopharyngeal carcinoma (NPC), characterized by the infiltration of lymphocytes, is a malignancy derived from the epithelium of the nasopharynx. Despite its sensitivity to radiation and chemotherapy, NPC has a high propensity for recurrence and metastasis. Although lymph node levels have been indicated as an independent prognostic factor for NPC, there has been no precise prognostic biomarker to predict clinical outcomes for NPC before advanced disease. In the present study, we surveyed differentially expressed genes in NPC via the next-generation sequencing (NGS)-based Oncomine database and identified the spindlin family member 4 (SPIN4) gene as the most relevant to advanced nodal status. We collected 124 tumor samples from NPC patients receiving biopsy, and the expression level of SPIN4 was evaluated by immunohistochemistry. The results showed that tumors with high SPIN4 expression were significantly correlated with advanced nodal status (p < 0.001) and advanced AJCC stages (p < 0.001). High SPIN4 expression in tumor samples was an unfavorable prognostic factor for all three endpoints at the univariate level: disease-specific survival (DSS), distal metastasis-free survival (DMeFS), and local recurrence-free survival (LRFS) (all p < 0.05). High SPIN4 expression remained independently prognostic of worse DMeFS (p = 0.049) at the multivariate level. Using bioinformatics analysis, we further found that high SPIN4 level may link tight junctions to cancer cell survival. Collectively, these results imply that high SPIN4 expression is linked to an aggressive clinical course, including advanced nodal status and poor survival in NPC patients, emphasizing the promising prognostic utility of SPIN4 expression. Full article

The chromatin reader protein Spindlin1 plays an important role in epigenetic regulation, through which it has been linked to several types of malignant tumors. In the current work, we report on the development of novel analogs of the previously published lead inhibitor A366. In an effort to improve the activity and explore the structure–activity relationship (SAR), a series of 21 derivatives was synthesized, tested in vitro, and investigated by means of molecular modeling tools. Docking studies and molecular dynamics (MD) simulations were performed to analyze and rationalize the structural differences responsible for the Spindlin1 activity. The analysis of MD simulations shed light on the important interactions. Our study highlighted the main structural features that are required for Spindlin1 inhibitory activity, which include a positively charged pyrrolidine moiety embedded into the aromatic cage connected via a propyloxy linker to the 2-aminoindole core. Of the latter, the amidine group anchor the compounds into the pocket through salt bridge interactions with Asp184. Different protocols were tested to identify a fast in silico method that could help to discriminate between active and inactive compounds within the A366 series. Rescoring the docking poses with MM-GBSA calculations was successful in this regard. Because A366 is known to be a G9a inhibitor, the most active developed Spindlin1 inhibitors were also tested over G9a and GLP to verify the selectivity profile of the A366 analogs. This resulted in the discovery of diverse selective compounds, among which 1s and 1t showed Spindlin1 activity in the nanomolar range and selectivity over G9a and GLP. Finally, future design hypotheses were suggested based on our findings. Full article