Promising Activity Research Articles

First-line zorifertinib for EGFR-mutant non-small cell lung cancer with central nervous system metastases: The phase 3 EVEREST trial.

Zorifertinib (AZD3759), an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) with high blood-brain barrier penetration capability, demonstrated promising intracranial and systemic antitumor activity in phase 1 and 2 studies in central nervous system (CNS)-metastatic patients. In this phase 3 EVEREST trial (ClinicalTrials.gov: NCT03653546), patients with EGFR-sensitizing mutations, advanced treatment-naive non-small cell lung cancer (NSCLC), and non-irradiated symptomatic or asymptomatic CNS metastases were randomized (1:1) to zorifertinib or first-generation EGFR-TKI (gefitinib or erlotinib; control). The primary endpoint was blinded independent central review (BICR)-assessed progression-free survival (PFS) per RECIST1.1. Overall, 439 patients were randomized (zorifertinib n= 220; control n= 219). Most patients had the EGFR L858R mutation (55%) or >3 CNS lesions (54%). Median PFS was significantly longer with zorifertinib versus control (9.6 versus 6.9months; hazard ratio [HR], 0.719; 95% confidence interval [CI], 0.580-0.893; p= 0.0024). Zorifertinib significantly prolonged intracranial PFS versus control (BICR per modified RECIST1.1: HR, 0.467; 95% CI, 0.352-0.619; investigator per RANO-BM: HR, 0.627; 95% CI, 0.466-0.844). Overall survival (OS) was immature; the estimated median OS was 37.3months with zorifertinib and 31.8months with control (HR, 0.833; 95% CI, 0.524-1.283) in patients subsequently treated with third-generation EGFR-TKIs. Safety profiles were consistent with previously reported data for zorifertinib. Zorifertinib significantly improved systemic and intracranial PFS versus first-generation EGFR-TKIs; adverse events were manageable. Sequential use of zorifertinib and third-generation EGFR-TKIs showed the potential to prolong patients' survival. The results favor zorifertinib as a novel, well-validated first-line option for CNS-metastatic patients with EGFR-mutant NSCLC. This work was funded by Alpha Biopharma (Jiangsu) Co., Ltd., China.

In silico Profiling and Pharmacokinetic Modelling of Olivetol: Evaluating its Potential as a Therapeutic Agent for Diabetic Wound Healing.

Diabetic wound healing poses a significant challenge due to the intricate disruptions in cellular and molecular processes induced by hyperglycaemia, leading to delayed or impaired tissue repair. Computational techniques offer a promising avenue for unravelling the complexities of diabetic wound healing by elucidating the molecular mechanisms involved. This study utilized in silico molecular docking and dynamics simulations to explore the potential therapeutic effectiveness of olivetol, a phenolic compound, in the context of diabetic wound healing. Furthermore, computational methodologies, encompassing pkCSM, Swiss ADME, OSIRIS® property explorer, PASS online web resource, and MOLINSPIRATION® software, were employed to forecast the pharmacokinetic properties, biological actions, and in vitro analyses, such as MTT and scratch assays, to evaluate the therapeutic effectiveness of olivetol in wound healing. Our findings have revealed olivetol to be a promising candidate for targeting multiple pathways implicated in diabetic wound healing. Its ability to modulate inflammation, oxidative stress, extracellular matrix remodeling, angiogenesis, and cell signaling suggests a multifaceted approach to promoting effective wound repair. Moreover, olivetol has been found to demonstrate strong binding affinity with key MRSA target proteins, indicating its potential as an antimicrobial agent against MRSA infections in diabetic wounds. The in vitro MTT assay demonstrated cell viability with an IC50 value of 40.80 μM, highlighting its cytotoxicity potential. Additionally, the scratch assay confirmed promising wound healing activity, showcasing its effectiveness in promoting cell migration and closure. Olivetol emerges as a promising candidate for targeted interventions in non-healing diabetic wounds, particularly due to its ability to address prolonged inflammation, a common obstacle in diabetic wound healing.

Purification and partial characterization of a new melibiose-specific lectin from Bauhinia catingae Harms

Lectins are ubiquitous proteins that selectively bind to carbohydrates, serving as vital models for understanding protein-carbohydrate interactions. While extensively distributed across various life forms, plant lectins, especially from the Leguminosae family, have garnered significant attention. However, limited research exists on lectins from the Caesalpinioideae subfamily, suggesting a source of untapped biotechnological potential. This underscores the imperative for further exploration, particularly in isolating lectins from the Bauhinia genus, which remains relatively understudied, despite harboring lectins with diverse characteristics and promising biotechnological activities. In this study, a novel lectin extracted from Bauhinia catingae Harms seeds (BCL) was isolated in three chromatographic steps. BCL exhibited affinity for galactose and derivatives, akin to other Bauhinia lectins, with SDS-PAGE confirming its molecular weight around 30 kDa. Notably, BCL demonstrated stability across temperature and pH ranges and lacked metalloprotein characteristics. Electrospray ionization mass spectrometry revealed a partial sequence covering 81 % of the total protein sequence with nearly 80 % identity to Bauhinia forficata. Structural analysis suggested a β-sheet-rich secondary structure similar to that of other lectins. Further structural elucidation of BCL is essential to unveil its full potential and applications.

Evaluation of antioxidant, antimicrobial, antidiabetic, anti-tyrosinase, and neuroprotective effects of β-ionone: In vitro and in silico analysis

β-Ionone is a bioactive phytochemical that has been extracted from many flowers, vegetables, and fruits. β-Ionone is an intriguing lead molecule from which several derivatives have been generated and exhibiting a variety of biological effects. Here, we investigated the β-Ionones’ antioxidant, anti-cholinesterases (AChE and BChE), anti-α-amylase, anti-α-glucosidase, and anti-tyrosinase activities. The antibacterial and antifungal effects were also studied. Moreover, in silico studies using molecular docking were carried out to understand the obtained results. The antioxidant activity performed by six different assays including phosphomolybdenum, CUPRAC, FRAP, DPPH, ABTS and metal chelating assay showed that β-Ionone exhibits a promising antioxidant activity. Besides, a good inhibition of AChE and BChE, as well as α-glucosidase, α-amylase, and tyrosinase was obtained. Molecular docking evidenced that β-Ionone correctly occupied the active site of the five studied enzymes through various kind of interactions which corroborate the in vitro outcomes. Moreover, in silico ADMET assessment showed that β-Ionone presented a good ADMET profile. Gram positive bacteria, specifically S. aureus (DIZ = 25 ± 1.5 mm; MIC = 6.25 mg/mL; CMB = 6.25 mg/mL) and B. cereus (DIZ = 21.5 ± 1 mm; MIC = 0.78 mg/mL; CMB = 0.78 mg/mL), showed greater susceptibility. Regarding Gram negative ones, P. aeruginosa exhibited also marked sensitivity (DIZ = 20.33 ± 1.5 mm; MIC = 12.5 mg/mL; CMB = 12.5 mg/mL). Additionally, β-Ionone can limit the growth of C. albicans (DIZ = 23 ± 1 mm; MIC = 1.56 mg/mL; CMB = 1.56 mg/mL). A bactericidal and fungicidal efficacy could be suggested as the MBC/MIC towards all the four inhibited pathogens was equal to 1. To sum up, data suggested that β-Ionone could have potential applications as an antioxidant, antimicrobial, and antifungal compound, as well as a potential inhibitor of tyrosinase, α-amylase, α-glucosidase, and cholinesterases. Furthermore, it can serve as a lead chemical in the creation of a new semisynthetic drug intended in order to treat numerous illnesses, including diabetes, Alzheimer’s disease, and pigmentation disorders

First-Line Tyrosine Kinase Inhibitors in Soft-Tissue Sarcomas: A Role for Anlotinib?

The optimal medical treatment of chemotherapy-ineligible patients affected by advanced soft-tissue sarcomas is unclear. In this population, tyrosine kinase inhibitors represent an appealing alternative treatment strategy. First-line use of the tyrosine kinase inhibitor anlotinib in chemotherapy-ineligible patients with soft-tissue sarcoma showed promising activity across multiple histologies. See related article by Li et al., p. 4310.

Electrochemical late-stage modification of hydralazine an antihypertensive drug. A green strategy for the synthesis of nano-structured new sulfonylhydrazine derivatives

This work is focused on the electrochemical late-stage modification of hydralazine (1-hydrazinylphthalazine) (HYD), a common antihypertensive drug, and the synthesis of its new sulfonylhydrazine derivatives. The synthesis of HYD derivatives has been easily accomplished in one-pot via electrochemical oxidation of HYD in the presence of arylsulfinic acid derivatives (ASA) in a water/ethanol mixture at constant current conditions. The electrochemical results show that anodically generated 1-diazenylphthalazine (HYDox) reacts with arylsulfinic acids and converts into the corresponding sulfonylhydrazine derivatives (SHD) with high yield and purity in an undivided cell equipped with graphite anode and stainless steel cathode. The main feature of this work is the synthesis of some new HYD derivatives in water/ethanol mixture as a “Green” reaction medium, using electrodes instead of toxic oxidants, having a high atom economy, having good energy efficiency and working at room temperature. These features are in accordance with the principles of green chemistry. Another advantage of this approach is that this method has led to the synthesis of sulfonylhydrazine derivatives in nano dimensions. Also, in this work, the electrochemical behavior of HYD and synthesized compounds (SHD) by different electrochemical methods were fully investigated and the results were reported. Furthermore, docking studies suggest that the products interact well with arylamine N-acetyltransferase (NAT) and show promising activity.

Structural characterization and bioactivity profiling of the fungal peptaibiotic tolypin reveal protective effects against influenza viruses.

In a bioprospection for new antivirals, we tested nonribosomally biosynthesized polypeptide antibiotics in MDCK II cells for their actions on influenza A and B viruses (IAV/IBV). Only tolypin, a mixture of closely related 16-residue peptaibiotics from the fungus Tolypocladium inflatum IE 1897, showed promising activity. It was selected for further investigation and structural characterization byultrahigh performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HR-MS/MS) and ultrahigh performance liquid chromatography coupled to in-source collision-induced dissociation tandem mass spectrometry (UHPLC-isCID-HR-MS/MS), revealing 12 partially co-eluting individual peptides that were fully sequenced. Since tolypin-related efrapeptins are potent inhibitors of F1/Fo-ATPase, we screened tolypin for its toxicity against MDCK II cells and larvae of the greater wax moth Galleria mellonella. We found that a nontoxic concentration of tolypin (1 µg/mL) reduced the titer of two IBV strains by 4-5 log values, and that of an H3N2 strain by 1-2 log values, but the H1N1pdm strain was not affected. The higher concentrations of tolypin were cytostatic to MDCK II cells, shifted their metabolism from oxidative phosphorylation to glycolysis, and induced paralysis in G. mellonella, supporting the inhibition of F1/Fo-ATPase as the mode of action. Our results lay the foundations for future work to investigate the interplay between viral replication and cellular energy metabolism, as well as the development of drugs that target host factors.

Structural Perspectives in the Development of Novel EGFR Inhibitors for the Treatment of NSCLC.

Non-small cell Lung cancer (NSCLC) is the most common type of lung cancer, which is caused by high consumption of tobacco and smoking. It is an epithelial lung cancer that affects about 2.2 million people across the globe, according to International Agency for Research on Cancer (IARC). Non-small cell lung cancer is a malignant tumor caused by EGFR mutation that occurs in the in-frame deletion of exon 19 and L858R point mutation in exon 21. Presently, clinically available inhibitors of EGFR (including erlotinib, lapatinib, gefitinib, selumetinib, etc.) are not specific and responsible for undesirable adverse effects. Moreover, to solve this problem search for newer EGFR inhibitors is the utmost need for the treatment and/or management of increasing lung cancer burden. The discovery of therapeutic agents that inhibit the specific target in tumorous cells, such as EGFR, is one of the successful strategies in treating many cancer therapies, including lung cancer. The exhaustive literature survey (2018-2023) has shown the importance of medicinally privileged pyrimidine derivatives together, fused and/or clubbed with other heterocyclic rings to design and develop novel EGFR inhibitors. Pyrimidine derivatives substituted with phenylamine, indole, pyrrole, piperazine, pyrazole, thiophene, pyridine and quinazoline derivatives substituted with phenylamine, pyrimidine, morpholine, pyrrole, dioxane, acrylamide, indole, pyridine, furan, pyrimidine, pyrazole etc. are privileged heterocyclic rings shown promising activity by inhibiting EGFR and TKIs. The present review summarizes the structure-activity relationship (SAR) and enzyme inhibitory activity, including IC50 values, percentage inhibition, and kinetic studies of potential compounds from various literature. The review also includes various aspects of molecular docking studies with compounds under clinical trials and patents filed on pyrimidine-based EGFR inhibitors in treating non-small cell lung cancer. The present review may benefit the medicinal chemist for developing novel compounds such as EGFR inhibitors.

Utilization of an optimized AlphaFold protein model for structure-based design of a selective HDAC11 inhibitor with anti-neuroblastoma activity.

AlphaFold is an artificial intelligence approach for predicting the three-dimensional (3D) structures of proteins with atomic accuracy. One challenge that limits the use of AlphaFold models for drug discovery is the correct prediction of folding in the absence of ligands and cofactors, which compromises their direct use. We have previously described the optimization and use of the histone deacetylase 11 (HDAC11) AlphaFold model for the docking of selective inhibitors such as FT895 and SIS17. Based on the predicted binding mode of FT895 in the optimized HDAC11 AlphaFold model, a new scaffold for HDAC11 inhibitors was designed, and the resulting compounds were tested in vitro against various HDAC isoforms. Compound 5a proved to be the most active compound with an IC50 of 365 nM and was able to selectively inhibit HDAC11. Furthermore, docking of 5a showed a binding mode comparable to FT895 but could not adopt any reasonable poses in other HDAC isoforms. We further supported the docking results with molecular dynamics simulations that confirmed the predicted binding mode. 5a also showed promising activity with an EC50 of 3.6 µM on neuroblastoma cells.

Design and synthesis of new coumarin-1,2,3-triazole hybrids as new antidiabetic agents: In vitro α-amylase, α-glucosidase inhibition, anti-inflammatory, and docking study

The current study focuses on the synthesis of coumarin-triazole hybrids (7i-t) starting from 4-hydroxy benzaldehyde or 4-hydroxyacetophenone (1a-b) and propargyl bromide. On the other hand, coumarin derivatives (5c-h) were prepared by Pechmann cyclization and treated with sodium azide to give the corresponding 3-azido methyl coumarins (6c-h). Finally, 1,3-dipolar cycloaddition between compounds 6c-h and terminal alkyne 2a-b produces coumarin-triazole hybrids (7i-t) utilizing click chemistry approaches that are high yielding, wide in scope and simple to perform. The structural proofs of the newly synthesized coumarin-triazole hybrids (7i-t) are proved by various spectroscopic techniques, including IR, 1H NMR, 13C NMR, and LC-MS. The synthesized new coumarin triazole hybrids (7i-t) were explored for their antihyperglycemic potential and therefore evaluated for α-glucosidase and α-amylase inhibitory activities along with anti-inflammatory. The results suggest that among the series, compound 7l showed excellent activity with an IC50 value of 0.67±0.014 mg/mL and 0.72±0.012 mg/mL for α-amylase, and α-glucosidase inhibitory potential while compound 7o showed promising anti-inflammatory activity with IC50 value of 0.54±0.003 mg/mL. To support the above findings, molecular docking studies were performed, which confirmed the interaction of the synthesized molecules 7i-t with an effective binding energy of -9.0 to -10.6 kcal/mol at the active site of the enzyme human pancreatic α-amylase (PDB ID: 1B2Y). Therefore, these scaffolds have the potential to function as lead candidates for antidiabetic and anti-inflammatory activities.

Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial

Ziftomenib (KO-539) is an oral selective menin inhibitor with known preclinical activity in menin-dependent acute myeloid leukaemia models. The primary objective of this study was to determine the recommended phase 2 dose in patients with relapsed or refractory acute myeloid leukaemia based on safety, pharmacokinetics, pharmacodynamics, and preliminary activity. KOMET-001 is a multicentre, open-label, multi-cohort, phase 1/2 clinical trial of ziftomenib in adults with relapsed or refractory acute myeloid leukaemia. Results of the phase 1 study, conducted at 22 hospitals in France, Italy, Spain, and the USA, are presented here and comprise the dose-escalation (phase 1a) and dose-validation and expansion (phase 1b) phases. Eligible patients were aged 18 years or older, had relapsed or refractory acute myeloid leukaemia, and had an Eastern Cooperative Oncology Group performance status of 2 or less. For phase 1a, patients (all molecular subtypes) received ziftomenib (50-1000 mg) orally once daily in 28-day cycles. For phase 1b, patients with NPM1 mutations or with KMT2A rearrangements were randomly assigned (1:1) using third-party interactive response technology to two parallel dose cohorts (200 mg and 600 mg ziftomenib). Primary endpoints were maximum tolerated dose or recommended phase 2 dose in phase 1a, and safety, remission rates, and pharmacokinetics supporting recommended phase 2 dose determination in phase 1b. Analyses were performed in all patients who received at least one dose of ziftomenib (modified intention-to-treat population). Phase 1a/1b is complete. This trial is registered with ClinicalTrials.gov, NCT04067336, and the EU Clinical Trials register, EudraCT 2019-001545-41. From Sept 12, 2019, to Aug 19, 2022, 83 patients received 50-1000 mg ziftomenib (39 [47%] were male and 44 [53%] were female). Median follow-up was 22·3 months (IQR 15·4-30·2). Of 83 patients, the most common grade 3 or worse treatment-emergent adverse events were anaemia (20 [24%]), febrile neutropenia (18 [22%]), pneumonia (16 [19%]), differentiation syndrome (12 [15%]), thrombocytopenia (11 [13%]), and sepsis (ten [12%]). Overall, 68 of 83 patients had serious adverse events, with two reported treatment-related deaths (one differentiation syndrome and one cardiac arrest). Differentiation syndrome rate and severity influenced the decision to halt enrolment of patients with KMT2A rearrangements. In Phase 1b, no responses were reported in patients treated at the 200 mg dose level. At the recommended phase 2 dose of 600 mg, nine (25%) of 36 patients with KMT2A rearrangement or NPM1 mutation had complete remission or complete remission with partial haematologic recovery. Seven (35%) of 20 patients with NPM1 mutation treated at the recommended phase 2 dose had a complete remission. Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukaemia. Phase 2 assessment of ziftomenib combination therapy in the upfront and relapsed or refractory setting is ongoing. Kura Oncology.

Design, Synthesis and Biological Evaluation of Novel Capsaicin Analogues Containing Heterocyclic Fatty Acids

AbstractThere is an urgent need to study safe and biocompatible medicinal compounds which necessitates the discovery of new agents from simple natural starting materials. In this study, eight novel capsaicin derivatives have been synthesized by combination of oxadiazole containing fatty acids with vanillyl amide. All the compounds were characterized by spectral analysis and were examined for their cytotoxicity, antimicrobial, antioxidant and anti‐inflammatory properties. The antioxidant activity of the synthesized derivatives was evaluated by 1,1‐diphenyl‐2‐picryl‐hydrazyl (DPPH) and thiobarbituric acid reactive substances (TBARS) assays. All of the synthesized derivatives have exhibited significant antioxidant activity in comparison to butylated hydroxy toluene (BHT) which is used as a reference antioxidant. The novel capsaicin derivatives with nitro (8 e) and methoxy substituents (8 f, 8 g and 8 h) exhibited the most significant antioxidant activity compared with BHT. In cytotoxicity assay against three cell lines, the derivative with bromo substituent showed excellent activity against B16‐melanoma cancer cell line followed by nitro and methoxy analogs which showed promising activity against HepG2‐ hepato and DU145‐prostate cancer cell lines respectively. In addition, all the derivatives exhibited moderate broad spectrum antibacterial, antifungal and anti‐inflammatory activity.

Prediction, Design, Synthesis, Insecticidal Activities of Polysubstituted Pyridine Anthranilic Amide Derivatives

Based on the predicted structure, a series of polysubstituted pyridine compounds containing 5-(furan-2-yl)-1H-pyrazole-3-carboxamido were designed and synthesized. These compounds were characterized using 1H NMR, 13C NMR, 19F NMR and HRMS. The results of the bioassays indicated that certain compounds exhibited promising activities against Mythimna separata and Plutella xylostella. It is noteworthy that compound I-6 exhibited 47% insecticidal activity at a concentration of 0.01 μg/mL, which reached the same activity level as chlorantraniliprole (CHL).Moreover, the cytotoxicity experiment showed compound I-26 demonstrated 50% larvicidal activity against M. separata at 10 μg/mL. Moreover, the toxicity of I-26 (IC50 0.007365 μg/mL) was superior to that of CHL (IC50 1.059 μg/mL). Furthermore, molecular docking was employed to predict the binding positions of the compounds, which demonstrated a good correlation between their insecticidal activities and their binding values. Finally, DFT calculations and molecular docking were employed to refine the binding sites of the ryanodine receptors in M. separata with CHL and I-24. The research laid a foundation for the innovation of RyR insecticides in the future.

Nivolumab plus ipilimumab with chemotherapy for non–small cell lung cancer with untreated brain metastases: A multicenter single-arm phase 2 trial (NIke, LOGiK 2004)

BackgroundThe effect of dual immunotherapy combined with platinum-based chemotherapy on untreated brain metastases derived from non–small cell lung cancer (NSCLC) has remained unclear. MethodsThis multicenter single-arm phase 2 study enrolled patients with chemotherapy-naïve advanced NSCLC and at least one brain metastasis ≥ 5 mm in size that had not been previously treated. Patients received nivolumab plus ipilimumab combined with platinum-doublet chemotherapy (two cycles), followed by nivolumab-ipilimumab alone. The primary endpoint of the study was intracranial response rate as determined by modified Response Evaluation Criteria in Solid Tumors (RECIST) for brain metastases of ≥ 5 mm as target lesions. ResultsA total of 30 patients from 18 institutions was enrolled in this study. The median age was 66.5 years (range, 47–83 years), and 26 patients (87 %) had a non–squamous cell carcinoma histology. The median size of all target brain lesions was 8.4 mm, with a range of 5–39 mm. The intracranial response rate assessed by modified RECIST was 50.0 % (95 % CI, 33.2–66.8 %), with the rate of complete response being 20.0 %, and the study met its primary endpoint. The systemic response rate was 53.3 % (95 % CI, 36.1–69.8 %), and responses for intracranial and extracranial lesions were generally consistent. The median intracranial progression-free survival was 8.1 months, and both the median intracranial duration of response and time to brain radiotherapy were not reached. ConclusionNivolumab plus ipilimumab combined with platinum-based chemotherapy showed promising intracranial activity in NSCLC patients with untreated brain metastases. Trial registrationjRCT071210019.

Cisplatin-Containing Combinations Associate with Survival in Women from Appalachian Kentucky with Metastatic, Persistent, or Recurrent Uterine Cervix Cancer.

Background: Prior preclinical studies showed promising antitumor activity and an acceptable safety profile associated with radiopharmaceuticals for patients with metastatic, persistent, or recurrent uterine cervix cancers. Whether the addition of a radiopharmaceutical to chemotherapy would significantly increase progression-free survival in such patients is untested. Our retrospective study sought to associate the line of treatment and progression-free survival as benchmarks for next-generation radiopharmaceutical development. Methods: We grouped metastatic, persistent, or recurrent uterine cervix cancer patients not amenable to curable surgery or radiotherapy between 2002 and 2023 by the line of doublet, triplet, and quadruplet chemotherapy or another intervention. After the first-line treatment, patients were monitored for radiographic progression every three months for up to three years. The primary endpoints were the first and any second or third progression-free survival intervals. Results: A total of 127 patients contributed demographic, tumor, line of treatment, and outcome data with a median follow-up of 18 months (25-75% interquartile range: 9 to 37 months). After the first-line treatment, 113 patients had local or distant progression or died from any cause, most often death from the disease (67%). Median progression-free survivals were 5.5 months (95% confidence interval: 4.8-6.0 months), 5.3 months (95% confidence interval: 4.5-6.3 months), and 3.0 months (95% confidence interval: 2.1-3.7 months) for the first-, second-, and third-line treatments, respectively. For a first-line cisplatin-containing regimen, the median progression-free survival was 6.5 months (95% confidence interval: 5.5-7.7 months). Conclusions: This study highlights the limited efficacy of current treatments for metastatic, persistent, or recurrent uterine cancer patients. A five-month progression-free survival might serve as a benchmark for the development of novel therapies in clinical efficacy trials, such as radiopharmaceuticals.

Nanostructured lipid carrier formulation for delivering poorly water-soluble ITF3756 HDAC inhibitor

Histone deacetylases (HDACs) are enzymes that play crucial roles in cellular processes by hydrolyzing acetyl-L-lysine side chains in core histones, thereby regulating gene expression and maintaining homeostasis. Histone deacetylase inhibitors (HDACi) have emerged as promising agents, particularly in cancer treatment, due to their ability to induce cytotoxic and pro-apoptotic effects. Selective HDAC6 inhibitors, such as ITF3756, have shown low off-target toxicity and promising pharmacological activities, but their poor water solubility limits their application in nanoparticulate drug delivery systems. Here, we optimized a nanostructured lipid carrier (NLC) formulation for delivering ITF3756 using the design of experiments (DOE) and response surface methodology (RSM). An interaction between the factor surfactant and formulation volume was observed, thus demonstrating that the surfactant concentration impacts the NLC size. It can be speculated that the higher the amount of the drug in the formulation, the lower the polydispersion index (PDI), thus resulting in more stable nanostructures. The optimized ITF3756-NLC demonstrated a size of 51.1 ± 0.3 nm, 8.85 ± 4.71 mV charge, and high entrapment efficiency (EE%), maintaining stability for 60 days. Moreover, ITF3756-NLC enhanced α-tubulin acetylation in melanoma, lung, and brain cancer cell lines, indicating retained or improved bioactivity. The ITF3756-NLC formulation offers a viable approach for enhancing the bioavailability and therapeutic efficacy of HDAC6 inhibitors, demonstrating potential for clinical applications in cancer immunotherapy.

(1,2,5,6-η)-Cyclo-octa-1,5-diene](1-ethyl-4-iso-butyl-1,2,4-triazol-5-yl-idene)(tri-phenyl-phosphane)iridium(I) tetra-fluorido-borate di-chloro-methane hemisolvate.

A new triazole-based N-heterocyclic carbene IrI cationic complex with a tetra-fluorido-borate counter-anion and hemi-solvating di-chloro-methane, [Ir(C8H12)(C8H15N3)(C18H15P)]BF4·0.5CH2Cl2, has been synthesized and structurally characterized. There are two independent ion pairs in the asymmetric unit and one di-chloro-methane solvent mol-ecule per two ion pairs. The cationic complex exhibits a distorted square-planar conformation around the IrI atom, formed by a bidentate cyclo-octa-1,5,diene (COD) ligand, a tri-phenyl-phosphane ligand, and an N-heterocyclic carbene (NHC). There are several close non-standard H⋯F hydrogen-bonding inter-actions that orient the tetra-fluorido-borate anions with respect to the IrI complex mol-ecules. The complex shows promising catalytic activity in transfer hydrogenation reactions. The structure was refined as a non-merohedral twin, and one of the COD mol-ecules is statistically disordered.

Identification of Key Immune and Cell Cycle Modules and Prognostic Genes for Glioma Patients through Transcriptome Analysis.

Gliomas, the most prevalent type of primary brain tumor, stand out as one of the most aggressive and lethal types of human cancer. To uncover potential prognostic markers, we employed the weighted correlation network analysis (WGCNA) on the Chinese Glioma Genome Atlas (CGGA) 693 dataset to reveal four modules significantly associated with glioma clinical traits, primarily involved in immune function, cell cycle regulation, and ribosome biogenesis. Using the least absolute shrinkage and selection operator (LASSO) regression algorithm, we identified 11 key genes and developed a prognostic risk score model, which exhibits precise prognostic prediction in the CGGA 325 dataset. More importantly, we also validated the model in 12 glioma patients with overall survival (OS) ranging from 4 to 132 months using mRNA sequencing and immunohistochemical analysis. The analysis of immune infiltration revealed that patients with high-risk scores exhibit a heightened immune infiltration, particularly immune suppression cells, along with increased expression of immune checkpoints. Furthermore, we explored potentially effective drugs targeting 11 key genes for gliomas using the library of integrated network-based cellular signatures (LINCS) L1000 database, identifying that in vitro, both torin-1 and clofarabine exhibit promising anti-glioma activity and inhibitory effect on the cell cycle, a significant pathway enriched in the identified glioma modules. In conclusion, our study provides valuable insights into molecular mechanisms and identifying potential therapeutic targets for gliomas.

Targeting the phosphatidylglycerol lipid: An amphiphilic dendrimer as a promising antibacterial candidate.

The rapid emergence and spread of multidrug-resistant bacterial pathogens require the development of antibacterial agents that are robustly effective while inducing no toxicity or resistance development. In this context, we designed and synthesized amphiphilic dendrimers as antibacterial candidates. We report the promising potent antibacterial activity shown by the amphiphilic dendrimer AD1b, composed of a long hydrophobic alkyl chain and a tertiary amine-terminated poly(amidoamine) dendron, against a panel of Gram-negative bacteria, including multidrug-resistant Escherichia coli and Acinetobacter baumannii. AD1b exhibited effective activity against drug-resistant bacterial infections in vivo. Mechanistic studies revealed that AD1b targeted the membrane phospholipids phosphatidylglycerol (PG) and cardiolipin (CL), leading to the disruption of the bacterial membrane and proton motive force, metabolic disturbance, leakage of cellular components, and, ultimately, cell death. Together, AD1b that specifically interacts with PG/CL in bacterial membranes supports the use of small amphiphilic dendrimers as a promising strategy to target drug-resistant bacterial pathogens and addresses the global antibiotic crisis.

Thoracic epithelioid inflammatory myofibroblastic sarcoma: a rare and aggressive disease with case report and literature review

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a rare subtype of inflammatory myofibroblastic tumor, characterized to be an aggressive disease with high frequency of ALK rearrangement, rapid recurrence, and poor prognosis. Primary EIMS of thoracic origin is rarely observed. Herein, we described a case of 28-year-old female developed primary EIMS in the anterior mediastinum with hepatic metastasis. The EIMS displayed sheet-like growth of epithelioid and spindle cells with enlarged nuclei, abundant and eosinophilic cytoplasm, and infiltration of inflammatory cells. Immunohistochemical staining revealed positive expression of ALK in the nuclear membrane, and ALK rearrangement was identified by polymerase chain reaction assay. Alectinib showed partial response, and achieved a meaningful survival benefit for four months. Based on this case report and literature review, ALK inhibitor reveals promising activity on the rare but aggressive EIMS. Awareness of EIMS in thoracic disease and its clinicopathological features is essential to avoid erroneous diagnosis.