Drug Development Research最新文献

Mitochondrial dynamics play a crucial role in glioma progression by regulating cellular metabolism, proliferation, and survival. This study investigated the effects of desmopressin (dDAVP), a synthetic vasopressin analog, on mitochondrial function in human U87 MG glioma cells. Our results demonstrate that dDAVP treatment induces dose-dependent cytotoxicity while upregulating vasopressin type 2 receptor expression. The compound significantly increased oxidative stress markers and impaired mitochondrial function, as evidenced by reduced ATP production, compromised respiratory chain activity, and decreased oxygen consumption. Furthermore, dDAVP promoted mitochondrial fragmentation through Drp1 activation, enhancing its phosphorylation at Ser616 and subsequent mitochondrial translocation. Mechanistically, dDAVP was found to activate CaMKII signaling, which mediated the observed changes in Drp1 phosphorylation and mitochondrial dynamics. The CaMKII inhibitor KN-93 effectively reversed dDAVP-induced mitochondrial fragmentation, Drp1 phosphorylation, and energy metabolism impairment. The AVPR2 antagonist tolvaptan blocked dDAVP effects, confirming receptor specificity. These findings reveal that dDAVP disrupts mitochondrial homeostasis in glioma cells through AVPR2-mediated CaMKII-dependent regulation of Drp1 activity, leading to mitochondrial dysfunction and cell damage. The study provides new insights into the molecular mechanisms underlying dDAVP's effects on glioma cells and suggests potential therapeutic applications targeting the CaMKII-Drp1 axis in glioma treatment.

Mitochondrial dysfunction critically underpins the pathogenesis of inflammatory skin diseases such as psoriasis, vitiligo, atopic dermatitis, and impaired wound healing. This comprehensive review synthesizes recent evidence to elucidate mechanisms, including compromised bioenergetics, excessive reactive oxygen species (ROS), mitochondrial DNA (mtDNA) damage, and aberrant mitochondrial dynamics. Distinct from prior work, this analysis uncovers novel findings: mtDNA acts as a damage-associated molecular pattern, activating cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathways to drive type I interferon in vitiligo and IL-17A in psoriasis; succinate-mediated immune-metabolic signaling amplifies type 2 inflammation in atopic dermatitis; and subclinical mitochondrial impairments in non-lesional skin serve as early indicators of disease susceptibility across these conditions. Preclinical studies have shown that emerging therapies, including antioxidants (e.g., NMN), mitochondrial modulators (e.g., SS31), senotherapeutics, and mitochondrial transplantation, are promising strategies for restoring cellular function. Future research should focus on multi-omics to dissect mitochondrial-epigenetic interactions, validate mitochondrial metabolites like succinate as diagnostic biomarkers, and explore synergistic combination therapies. This integrative framework of mitochondrial-driven pathology provides fresh perspectives to advance diagnostic and therapeutic innovation in dermatology.

The epidermal growth factor receptor (EGFR) is a key target in cancer therapy, mainly in non-small cell lung cancer (NSCLC). Though, the efficacy of EGFR-targeted therapies is limited by the development of resistance. This comprehensive review details the structural biology of EGFR and its role in oncogenic signaling, elucidating the major activating mutations, particularly exon 19 deletions and L858R point mutations, and acquired resistance. The progressive development of EGFR tyrosine kinase inhibitors (TKIs), from first-generation ATP-competitive inhibitors (e.g., gefitinib, erlotinib) to third-generation covalent agents (e.g., osimertinib) and emerging fourth-generation allosteric and degradation approaches, are critically examined for their mechanisms, efficacy, and clinical limitations. We have also discussed about the intrinsic and acquired resistance mechanisms, including alternative oncogenic drivers (KRAS, ALK), bypass pathway activations (MET, HER2), and phenotypic changes like epithelial-mesenchymal transition. Additionally, we emphasize the role of computational modeling, high-throughput SAR studies, and preclinical models, including patient-derived xenografts and organoids, in guiding rational drug design. Emerging approaches integrating artificial intelligence, machine learning, and precision oncology hold potential to accelerate EGFR-targeted drug discovery. The combination strategies with immunotherapy, and anti-angiogenic agents are considered in the context of improving patient outcomes. Together, ongoing advances in understanding EGFR signaling and resistance mechanisms are driving the development of next-generation inhibitors and personalized therapies, with the ultimate goal of overcoming drug resistance and improve patient outcomes in EGFR-mutant cancers.

In this study, nine new synthesized compounds were investigated for their enzyme inhibition activity and evaluated for their ADME parameters and DFT-based properties. The compounds were classified into two main structures: derivatives of 2-(3/4-chlorophenoxy)-N-(3-(4-chlorophenyl)-4-(4-substituted phenyl)thiazol-2(3H)-ylidene)propanehydrazide (4a-4f) and N-(6-substituted benzothiazol-2-yl)-2-((5-(1-(3-chlorophenoxy)ethyl)-4-(4-chlorophenyl)-4H-1,2,4-triazol-3-yl)thio)acetamide (6a-6c). The inhibitory effects of these compounds on cholinesterase and MAO enzymes were studied, and their percentages of inhibition were determined. It was found that the compounds exhibited higher inhibition of AChE than BChE, with compounds 4e, 6a, and 6b showing the highest percentage inhibition against AChE. In terms of MAO inhibition, compounds 6a and 6b demonstrated significant potency against MAO-A, while compounds 4a, 4 d, 4 f, and 6c exhibited inhibition against MAO-A above 55.372%. The compounds also showed notable inhibition against MAO-B, with compounds 4a, 4 f, 6a, and 6b displaying the highest inhibitory activity. DFT studies revealed the optimized molecular structures and the energy difference between the HOMO and LUMO orbitals. Compound 4a exhibited greater activity and compound 4 f showed nucleophilic character, while compound 6a displayed higher electronegativity and nucleophilic character. In silico analyses indicated that the benzothiazole moiety was localized at the outer region of the MAOs, whereas the phenoxy and 4-chlorophenyl moieties were positioned near the FAD cofactor within the inner pocket. It was also suggested that the acyl moiety is pivotal in forming H-bonds with the key residues. These findings contribute to the understanding of the enzyme inhibition activity and molecular properties of the azole-based ether derivatives in modulation of neuroprotective enzymes.

In this study, eight 3-substitued -4-amino-4,5-dihydro-1H-1,2,4-triazol-5-one compounds were synthesized. The reactions of these compounds with 2-ethoxy-4-formylphenyl benzoate, which was synthesized by the reaction of 3-ethoxy-4-hydroxy benzaldehyde with benzoyl chloride by using triethylamine, were investigated. Eight novel 2-ethoxy-4-(((3-substitued-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)imino)methyl)phenyl benzoate compounds were obtained in order to identify the new synthesized compounds by spestroscopic methods including IR, ¹H-NMR and ¹³C-NMR used. Concentration ranges of 25, 50, 120, 200, and 400 µg/mL were applied to determine the compund's anti-cancer properties. The human ovarian cancer cell line (OVCAR-3) compared with human umbilical vein endothelial cells (HUVEC) and significant results were obtained against the OVCAR-3 cell line. The enzyme inhibitory effect of compound on glutathione S-transferase (GST), acetylcholinesterase (AChE) enzymes were studied. Ki and IC₅₀ values were found in the range of 1.1143 ± 0.2402 µM–7.9100 ± 1.9107 µM and 1.840 µM–4.149 µM for AChE; 2.0733 ± 0.8199 µM–8.2120 ± 1.5720 µM and 1.320 µM–3.223 µM for GST. In silico ADMET and drug-likeness analyses confirmed favorable pharmacokinetic and drug-like profiles for the compounds. Additionally, molecular docking and 100 ns molecular dynamics (MD) simulations revealed stable binding modes and dynamic stability of the most active compounds with the target enzymes.

DNA polymerase theta (POLθ) has been regarded as a promising therapeutic target for the treatment of BRCA-deficient tumors. In this study, 1-(arylacetyl)-2-phenyl-pyrrolidine derivative VS-13 was identified as a POLθ-pol inhibitor hit with an IC₅₀ value of 1.47 μM through virtual screening. The followed similarity research obtained a more potent analogue SS-5, which was hybridized with RP-6685 to get 1-(phenylacetyl)-2-phenyl-pyrrolidine derivative F-1. It showed potent POLθ inhibitory activity with an IC₅₀ value of 170 nM, and good anti-proliferative activity against BRCA2-deficient DLD1 and HCT116 cell lines, with IC₅₀ values of 4.39 μM and 4.79 μM, respectively. Further MD simulations and interaction analysis disclosed the possible binding mode of F-1 with POLθ-pol.

In this study, three series of pyrazole and pyrazolo[1,5-a]pyrimidine derivatives 6a-f, 8a-f, and 10a-f were designed and synthesized in response to the global need to safe and potent anti-inflammatory agents. A rational design strategy was employed to synthesize compounds that inhibit inflammation-related carbonic anhydrase isoforms (II, IX, and XII) alongside achieving selective inhibition of cyclooxygenase-2 (COX-2). Remarkably, the sulfonamide derivatives 6f, 8d, and 10e displayed high activity as carbonic anhydrase inhibitors against isoforms II, IX and XII in addition to their potent and selective COX-2 inhibition effect (IC₅₀ = 57–87 nM; SI = 175–100). Among them, the multitargeted inhibitor 10e (COX-2, IC₅₀ = 57 nM; CA II, K_i = 49.9 nM; CA IX, K_i = 67.5 nM; CA XII, K_i = 54.6 nM) was further evaluated in vivo and demonstrated strong dual anti-inflammatory and analgesic properties, with a rapid onset of action within the first hour and sustained efficacy over 5 h. Toxicological studies revealed that compound 10e possessed a favorable safety profile, showing no significant adverse effects on liver, kidney, or cardiac functions and minimal ulcerogenic potential. Molecular docking studies further supported these findings by confirming key binding interactions with CA II, IX, XII, and COX-2 active sites.

Glioblastoma is the most common and aggressive malignant brain tumor, characterized by poor response to current therapies and inevitable recurrence. Novel therapeutic strategies are urgently needed. Lansbermin-I, a disintegrin isolated from the venom of Porthidium lansbergii lansbergii, was purified, sequenced, structurally modeled, and evaluated for its antitumor potential against the human Glioblastoma cell line T98G. Cytotoxicity assays revealed a dose-dependent effect, with Lansbermin-I inducing up to 38.1% cell death at 100 μg/mL, surpassing the activity of temozolomide (34.9%) while exhibiting lower toxicity on non-tumorigenic human astrocytes (28% vs. 37%). Lansbermin-I also inhibited T98G adhesion to fibronectin by nearly 80% (p < 0.0001), suggesting interference with integrin-mediated interactions. Flow cytometry demonstrated a significant increase in apoptotic cells (60% vs. 36% in control) and cell cycle arrest at the G1 phase. In silico docking studies supported a strong interaction of Lansbermin-I with integrin αvβ3, comparable to that of fibronectin, reinforcing its potential mechanism of action through the disruption of adhesion and survival signaling. Collectively, these findings highlight Lansbermin-I as a promising selective prototype for Glioblastoma therapy. Further studies are warranted to elucidate its molecular targets and evaluate its efficacy in preclinical models.