Drug Development Research最新文献

The abnormal overexpression of FLT3 kinase is intimately associated with pathogenesis of acute myeloid leukemia (AML), positioning FLT3 inhibitors as pivotal therapeutic agents. Despite the availability of three FDA-approved FLT3 inhibitors, their clinical utility is hampered by resistance stemming from tyrosine kinase domain (TKD) mutations. Through an integrative analysis of case studies, we identified a potential advantage of type I FLT3 inhibitors in overcoming TKD mutation-induced resistance. Structure–activity relationships (SAR) analysis indicated that FW-1 exhibited over 50% inhibition against FLT3 at a concentration of 1 μM and demonstrated potent activity against AML cell lines MV4-11 (IC₅₀ = 2.68 μM) and MOLM-13 (IC₅₀ = 1.03 μM). In our cellular mechanistic studies, FW-1 also effectively induced apoptosis by arresting cell cycle progression in the G0/G1 phase. This study introduces FW-1 as a promising lead for type I FLT3 inhibitor, warranting further optimization.

Cell membrane-coated Nano-Liposomes (CM-NLPs) offer a promising approach that combines the advantages of both host cells and synthetic nano-liposomes (NLPs). This technique involves coating liposomes with red blood cell (RBC) membranes to enhance their functionality. In this study, novel carboplatin-loaded NLPs (CP-NLPs) were formulated using phospholipids (Soya Phosphatidyl Choline) and cholesterol through the thin-film hydration method, and optimized using a 3² full factorial design. The optimized CP-NLPs were coated with RBC membranes, resulting in the formulation “CP-RBCs-NLPs.” These were characterized for particle size, zeta potential, entrapment efficiency, transmission electron microscopy (TEM), differential scanning calorimetry (DSC), protein content, in vitro drug release, cell viability, and stability. The optimized CP-RBCs-NLPs exhibited a particle size of 103.6 nm, with zeta potential values of −27.3 mV indicating good stability. The entrapment efficiency was approximately 56%, and the drug release profile showed sustained release for up to 8 h. Cytotoxicity studies in human triple-negative breast cancer (MDA-MB468) cell lines demonstrated that CP-RBCs-NLPs effectively delivered the drug into target cells, facilitating cell death due to their bilayer structure similar to cell membranes. Overall, CP-RBCs-NLPs outperformed both carboplatin-loaded conventional NLPs (CP-CNLPs) and carboplatin-conventional solution (CP-CNS), making it a superior formulation for drug delivery.

Mortalities due to mycoses have dramatically increased with the emergence of drug-resistant strains and growing immune-compromised populations globally. Azole antifungals have been the first choice against fungal infections of a wide spectrum and several azole derivatives with ester function were reported for their potentially promising and favorable activity against Candida spp. In this study, we designed and synthesized a series of 1-(aryl)−2-(1H-imidazol-1-yl/1H-1,2,4-triazol-1-yl)ethyl esters, and tested them against seven reference Candida strains using EUCAST reference microdilution method. Among the series, 6a, 6d, and 6g proved highly potent in vitro compared to fluconazole; especially against Candida albicans and Candida tropicalis with minimum inhibitor concentration (MIC) values as low as 0.125 and 0.06 mg/L, respectively, although their activities against Candida krusei and Candida glabrata remained limited. The compounds also showed minimal toxicity to murine fibroblasts according to the in vitro cytotoxicity tests. Molecular modeling predicted 6g as an orally available druglike compound according to all parameters and CYP51 inhibition as the likely mechanism for their antifungal effects. The study underpins the promise of azoles with ester functionality as a potential scaffold for small-molecule antifungal drug design.

Ambroxol (ABX) is used to manage excessive production of mucus in the respiratory system. The present study sought to assess the neuroprotective potential of ambroxol by influencing the amyloidogenic, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways in a rat model of Alzheimer's disease (AD) induced by scopolamine. The AD pathology was induced by chronic administration of scopolamine. The rats were given scopolamine at a dose of 2 mg/kg via intraperitoneal injection daily for 14 days, followed by treatment (ABX 121.5, 135, and 180 mg/kg orally and 5 mg/kg orally of donepezil) for the next 28 days while continuing to receive daily scopolamine injection. The behavior of the rats was evaluated using Modified Y-Maze and Novel object recognition tasks. Analyses were carried out on AD pathological markers [Amyloid beta peptide 1-40, Amyloid beta peptide 1-42, acetylcholinesterase, beta-secretase 1 (BACE1), total tau, and p-tau], inflammatory markers [NF-κB, tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interferon γ], antioxidant markers (Nrf2 and heme Oxygenase 1 (HO-1)], along with synaptophysin and glial fibrillary acidic protein (GFAP) immunohistochemistry and histopathological assessment of the hippocampus. Our findings indicated that ABX reduced impairment in behavior. Levels of Acetylcholinesterase, BACE1, amyloid beta 1-40, amyloid beta 1-42, total tau, p-tau, NF-κB, IFN-γ, IL-6, and TNF-α decreased significantly. There was a significant increase in the levels of HO-1 and Nrf2. It stopped the neuronal degeneration, raised synaptophysin immunoreactivity, and lowered GFAP immunoreactivity. The current research indicates that ambroxol may possess senomorphic properties by impacting the transcription factors NF-κB and senescence-associated secretory phenotype (SASP). Consequently, it could provide neuroprotection through alterations in the Nrf2 and NF-κB signaling pathways in AD.

Inhibition of SIRT3 triggered differentiation of multiple myeloma (MM) cells. In discovery of potent SIRT3 inhibitors for cancer differentiation therapy, structural modification was performed on the previously developed lead compound S27. A total of 49 compounds divided into two series were designed and synthesized. In the enzyme inhibitory assay, several molecules (A7, A13, B15, and B26) exhibited potent SIRT3 inhibitory activity and selectivity. Significantly, representative compounds, especially A7, promoted differentiation of MM cells from cancer phenotype to normal cells, accompanied by increased expression of antigen CD49e, human immunoglobulin light chain λ-IgLG and κ-IgLG. Additionally, molecule A7 reversed growth factor IL-6 induced MM cell proliferation, improved the antiproliferative activity of Ixazomib and increased the apoptotic rate of MM cells treated with Ixazomib. Collectively, potent SIRT3 inhibitors with MM cell differentiation potency were developed for the cancer therapy used alone or in combination.

Osteoarthritis (OA), a disease of articular joints, is the leading cause of disability in the elderly. Repressing ferroptosis and improving mitochondrial function can delay the progression of OA. Kruppel-like factor 2 (KLF2) exerts a protective effect on OA. However, whether KLF2 affects ferroptosis and mitochondrial function during OA remains unknown. The OA in vivo and in vitro models were constructed in this work. The structural damage of knee joint in OA mice was evaluated through Micro-CT scanning. H&E, SOFG, TB, and TUNEL staining were applied for pathological examination of cartilage tissues. ELISA was employed to examine the contents of inflammatory factors. Additionally, iron deposition in cartilage tissues was measured by Prussian blue staining, and the levels of proteins related to ferroptosis were assessed by immunoblotting. Besides, mitochondrial morphology and function were estimated using a transmission electron microscope and JC-1 staining. In interleukin (IL)-1β-treated C28/I2 cells, the levels of inflammatory factors, intracellular ROS, mitochondrial ROS, lipid ROS, and Fe²⁺ were measured. Mitochondrial function was evaluated by detecting the levels of mitochondrial membrane potential (MMP), ATP, mPTP, and OCR. KLF2 overexpression ameliorated the structural damage of knee cartilage in OA mice. KLF2 upregulation inhibited ferroptosis and alleviated mitochondrial damage in knee cartilage of OA mice and IL-1β-treated C28/I2 cells. Moreover, KLF2 overexpression activated SIRT1/GPX4 signaling in vivo and in vitro. EX527 addition blocked the influences of KLF2 upregulation on ferroptosis and mitochondrial dysfunction in IL-1β-treated C28/I2 cells. Altogether KLF2 inhibits ferroptosis and improves mitochondrial dysfunction in chondrocytes through SIRT1/GPX4 signaling to improve OA.

Gastrointestinal cancer has emerged as a significant global health concern due to its high incidence and mortality, limited effectiveness of early detection, suboptimal treatment outcomes, and poor prognosis. Metabolic reprogramming is a prominent feature of cancer, and fatty acid metabolism assumes a pivotal role in bridging glucose metabolism and lipid metabolism. Fatty acids play important roles in cellular structural composition, energy supply, signal transduction, and other lipid-related processes. Changes in the levels of fatty acid metabolite may indicate the malignant transformation of gastrointestinal cells, which have an impact on the prognosis of patients and can be used as a marker to monitor the efficacy of anticancer therapy. Therefore, targeting key enzymes involved in fatty acid metabolism, either as monotherapy or in combination with other agents, is a promising strategy for anticancer treatment. This article reviews the potential mechanisms of fatty acid metabolism disorders in the occurrence and development of gastrointestinal tumors, and summarizes the related potential biomarkers and anticancer strategies.

Polyadenosine diphosphate-ribose polymerase 7 (PARP7) acts as a suppressor of the type I interferon (IFN) signaling pathway via suppressing TANK-binding protein 1 (TBK1). Research study indicates that inhibition of PARP7 could potentially regulate tumor immunity. However, the effect of PARP7 inhibition on innate antiviral immunity in macrophages as well as the underlying mechanism have not been demonstrated else well. We report herein that PARP7 inhibitor clinical candidate RBN-2397 could augment type I interferon (IFN-I) production in macrophages by elevating retinoic acid-inducible gene I (RIG-I) and stimulator of interferon genes (STING) signaling pathways. Treatment with RBN-2397 leads to increased pattern recognition ligands-induced interferon-β production in primary bone marrow-derived macrophages (BMDM) and RAW264.7 cells. Additionally, RBN-2397 suppresses viral replication efficiency in macrophages infected by vesicular stomatitis virus (VSV) and amplifies the expression of interferon-stimulated chemokine genes (ISGs). Mechanistically, RBN-2397 promotes TBK1 phosphorylation, consequently leading to the amplified activation of RIG-I and STING signaling pathways. Furthermore, RBN-2397 enhances the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2 induced by IFN-α/β and the expression of chemokine genes in macrophages in response to IFN stimulation. In vivo experiments demonstrated that RBN-2397 enhances innate antiviral immunity in mice infected with VSV, resulting in increased serum IFN-β levels, reduced viral loads, and alleviated pulmonary inflammatory responses of the VSV-infected mice. In conclusion, our findings highlight the potential of RBN-2397 as a promising antiviral therapeutic agent for enhancing the IFN-relative antiviral immune defense in host.