Drug Development Research[JOURNAL]
Sun
200 papers
Discovery of Novel 1,3,5-trisubstituted-2-thioxo-imidazole Derivatives as Potential Aromatase Inhibitors: Design, Synthesis, In Vitro Anti-Breast Cancer Screening and Molecular Docking Studies.
Youssef MF, Hasanen JA, Shehata AA … +3 more , Saleh AM, Rizzk YW, Abdallah AM
Drug Dev Res · 2026 Apr · PMID 41685911 · Publisher ↗
Imidazole derivatives have a multi-targeted ability that indicates their ability to act as anticancer agents in respect to breast cancer. This study aimed to evaluate the anticancer response of a new series of 1, 3, 5-tr...
Imidazole derivatives have a multi-targeted ability that indicates their ability to act as anticancer agents in respect to breast cancer. This study aimed to evaluate the anticancer response of a new series of 1, 3, 5-trisubstituted-2-thioxo-imidazoles derivatives (5-8) in vitro. The structural elucidation was performed with the usage of IR, ¹H-NMR and ¹³C-NMR. Compounds 6b and 8b had significant anti-cytotoxic activity in the MCF-7 cell line and had IC values of 5.316 µg/mL and 2.805 µg/mL where they had minimal toxicity on normal cells (MCF-10A). The mechanistic studies have shown that compound 6b and 8b were very effective in stopping the cell cycle at the G1 stage and also the induction of apoptosis. Moreover, the compounds 6b and 8b depicted in the paper displayed an inhibitory action concerning the aromatase enzyme. The results of qRT-PCR implied that both compounds 6b and 8b exerted a considerable apoptotic impact in the manner in which they up-regulated caspase-9 and p53 and down-regulated Bcl-2. The binding interaction mechanisms between the docked compounds and aromatase enzyme and Bcl-2 receptors were better understood in terms of a molecular docking analysis. Altogether, the results of the present study suggest that the 1, 3, 5-trisubstituted-2-thioxo-imidazole backbone can be used as a promising new scaffold in future development of multi-action anti-cancer drugs in breast cancer.
Innovative Drug and Prodrug Candidates in Cancer Treatment Targeting TP53 Mutations: Challenge and Hope.
Al-Zoubi RM, Elaarag M, Zarour AA … +12 more , Garada K, Al-Zoubi SR, Fares ZE, Al-Qudimat AR, Shkoor M, Khan A, Sawali MA, Bawadi H, Zakaria ZZ, Zoubi MA, Agouni A, Alrumaihi K
Drug Dev Res · 2026 Apr · PMID 41665206 · Publisher ↗
The TP53 gene encodes the tumor suppressor protein 53, which is critical for maintaining genomic stability and preventing tumorigenesis. Mutations in TP53, particularly missense mutations, have a substantial impact on ca...
The TP53 gene encodes the tumor suppressor protein 53, which is critical for maintaining genomic stability and preventing tumorigenesis. Mutations in TP53, particularly missense mutations, have a substantial impact on cancer progression because they give gain-of-function features that enhance proliferation, metastasis, and treatment resistance. This review examines the mechanisms underlying p53 mutations, including their interactions with critical regulatory circuits, and assesses novel medication and prodrug options targeting TP53 mutations in various malignancies. Small-molecule correctors, statins, Hsp90 inhibitors, and new drugs like Eprenetapopt and COTI-2 are among the therapeutic options proposed. The mechanisms of action and potential efficacy in treating leukemia, lung, breast, and ovarian malignancies are investigated. Emerging techniques for restoring wild-type p53 functionality or degrading mutant p53 demonstrate the therapeutic potential of these approaches. Challenges such as medication resistance, side effects, and the chemical complexity of p53 pathways are also addressed, emphasizing the importance of ongoing research. This review contributes to our understanding of TP53-targeted cancer medicines, offering hope for more innovative treatments with improved outcomes.
Azole Amide Analogues as Antibacterial Agents Against Methicillin-Resistant Staphylococcus aureus and Its Structure-Activity Relationship Studies.
Sharma S, Verma R, Verma SK … +5 more , Thakur PK, Singh MV, S D, Rakesh KP, Kumar KSS
Drug Dev Res · 2026 Apr · PMID 41660768 · Publisher ↗
Methicillin-resistant Staphylococcus aureus (MRSA) is a well-known cause of serious skin and soft tissue infections, representing a significant global public health threat. The rapid development of MRSA resistance to all...
Methicillin-resistant Staphylococcus aureus (MRSA) is a well-known cause of serious skin and soft tissue infections, representing a significant global public health threat. The rapid development of MRSA resistance to all known antibiotics is the biggest concern. Therefore generating new anti-MRSA agents is the need of the present hour. Azoles combined with amides are well-known structures for developing compounds that exhibit antimicrobial effects against MRSA. Molecular hybridization, which involves combining various heterocyclic pharmacophores into a single molecular hybrid, offers a promising way for creating new antibacterial agents. In view of this, numerous attempts were made to incorporate various heterocyclic systems into azole nucleus bearing amide groups, which were then tested for antibacterial activity. This review outlines the advancements made over the past ten years regarding azole amide derivatives that exhibit extensive antibacterial properties against various MRSA strains. Specifically, we focused on the antibacterial property of structurally diverse azole analogues, such as thiazole, imidazole, oxadiazole, triazole, and pyrazole amides against MRSA and examined structure-activity relationship (SAR) studies.
Dehydrocorydaline in Corydalis Yanhusuo Promotes M2 Microglial Polarization and Alleviates Neuroinflammation After Cerebral Ischemia-Reperfusion Injury by Inhibiting the JAK1/STAT3 Pathway.
Wei L, Yu Y, Hu L … +2 more , Zhang F, Gao L
Drug Dev Res · 2026 Apr · PMID 41649838 · Publisher ↗
Ischemic stroke is the third leading cause of death and disability worldwide. Cerebral ischemia-reperfusion injury leads to severe neuroinflammation, in which microglial polarization plays a key role. Dehydrocorydaline (...
Ischemic stroke is the third leading cause of death and disability worldwide. Cerebral ischemia-reperfusion injury leads to severe neuroinflammation, in which microglial polarization plays a key role. Dehydrocorydaline (DHC), the main alkaloid of Corydalis yanhusuo, has anti-inflammatory and neuroprotective effects. However, it is unknown if it controls microglial polarization to lessen cerebral ischemia-reperfusion injury. A mouse middle cerebral artery occlusion (MCAO) model and an in vitro microglial oxygen-glucose deprivation/reoxygenation (OGD/R) model were used. 2,3,5-triphenyltetrazolium chloride (TTC) staining, neurological function scores, flow cytometry, Enzyme-Linked Immunosorbent Assay, and Western blot were used to evaluate the efficacy and mechanism of DHC. A rescue experiment was also conducted using the Janus Kinase 1 (JAK1) agonist coumermycin A1 (CMA1). Compared with the MCAO group, DHC treatment significantly reduced cerebral infarction volume and significantly improved neurological function scores, motor coordination, and sensorimotor function. DHC effectively reduced hippocampal neuronal damage. At the same time, DHC treatment significantly decreased the level of pro-inflammatory factors in brain tissue, while increasing the level of anti-inflammatory factors. DHC significantly reduced the expression of M1 phenotype markers and upregulated the expression of M2 phenotype markers. Mechanistically, DHC significantly inhibited the phosphorylation levels of JAK1 and Signal Transducer and Activator of Transcription 3 (STAT3), while the JAK1 agonist CMA1 completely reversed the above-mentioned protective effects of DHC. DHC reduces neuroinflammation and has a neuroprotective impact against cerebral ischemia-reperfusion injury by blocking the JAK1/STAT3 signaling pathway and encouraging microglia to polarize to the M2 phenotype.
Bulk Microarray and Single-Cell Transcriptomic Analyses Reveal Bacterial Lipopolysaccharide-Related Biomarkers in Sepsis.
Zhang H, Wu X, Wu L … +2 more , Ma L, Duan L
Drug Dev Res · 2026 Apr · PMID 41649833 · Publisher ↗
Sepsis, a life-threatening condition triggered by dysregulated host response to infection, poses significant global health challenges. Identifying lipopolysaccharide (LPS)-related biomarkers and underlying mechanisms rem...
Sepsis, a life-threatening condition triggered by dysregulated host response to infection, poses significant global health challenges. Identifying lipopolysaccharide (LPS)-related biomarkers and underlying mechanisms remains critical, yet underexplored. We integrated bulk microarray datasets and single-cell RNA-seq data from the Gene Expression Omnibus to identify LPS-related genes associated with sepsis. scRNA-seq was used for cell clustering, annotation, AUCell scoring, and cell-cell communication analysis. Differentially expressed LRGs were screened from both bulk and single-cell datasets and intersected. Three machine learning algorithms-least absolute shrinkage and selection operator regression, support vector machine-recursive feature elimination, and extreme gradient boosting-were applied to select robust diagnostic biomarkers. Gene expression was validated via qRT-PCR. Diagnostic and prognostic models were constructed and validated in independent cohorts. Seven key LRGs were identified. The diagnostic model achieved high AUCs (> 0.89) across validation cohorts, while the prognostic model effectively stratified patients into distinct survival groups. High-risk groups showed increased myeloid-derived suppressor cell and macrophage infiltration, activation of inflammatory pathways, and unique intercellular communication networks. scRNA-seq revealed cell-type-specific LRGs expression, particularly in myeloid populations. We established and validated a robust LPS-related biomarker model that integrates bulk microarray and single-cell transcriptomics, offering novel diagnostic, prognostic, and therapeutic insights for sepsis.
AAV9-Delivered α7nAChR Ameliorates DSS-Induced Murine Ulcerative Colitis by Activating CAP Pathway, Inhibiting NF-κB/NLRP3 Axis and Restoring Intestinal Barrier and T-reg/Th-17 Homeostasis.
Zhang R, Yang Q, Bi H
Drug Dev Res · 2026 Apr · PMID 41637679 · Publisher ↗
This study aimed to explore the therapeutic effect and underlying mechanism of α7 nicotinic acetylcholine receptor (α7nAChR) mediated by adeno-associated virus serotype 9 (AAV9) on dextran sulfate sodium (DSS)-induced ul...
This study aimed to explore the therapeutic effect and underlying mechanism of α7 nicotinic acetylcholine receptor (α7nAChR) mediated by adeno-associated virus serotype 9 (AAV9) on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice. Male C57BL/6 mice were randomly divided into the blank control group, model group, AAV-α7nAChR low/medium/high-dose groups, and AAV-GFP group. A chronic UC model was established, with interventions administered via intraperitoneal injection. Meanwhile, an acute UC model was set up, together with control groups treated with the α7nAChR antagonist methyllycaconitine (MLA) and 5-aminosalicylic acid (5-ASA). A series of indicators were detected, including body weight, Disease Activity Index (DAI), colonic pathological changes, inflammatory factors, pathway-related proteins, and T-regulatory (T-reg)/T helper 17 (Th-17) cell balance. Results demonstrated that AAV9-α7nAChR ameliorated UC symptoms in mice in a dose-dependent manner: it relieved body weight loss and hematochezia, restored colon length and spleen weight, and alleviated colonic mucosal damage. Furthermore, it activated the cholinergic anti-inflammatory pathway (CAP), inhibited the NF-κB/NLRP3 inflammatory axis, repaired the intestinal barrier (by upregulating ZO-1 and occludin), and restored the T-reg/Th-17 immune balance. The therapeutic efficacy of the high-dose AAV9-α7nAChR group was superior to that of the 5-ASA group, while MLA could suppress its therapeutic effect. This study preliminarily clarified the multi-target mechanism of AAV9-α7nAChR in treating UC, providing an experimental foundation for the clinical gene therapy of UC.
Corrigendum to "Lansbermin-I: A Snake Venom Disintegrin With Selective Cytotoxicity and Anti-Adhesive Effects against Glioblastoma Cells".
Drug Dev Res · 2026 Apr · PMID 41637666 · Publisher ↗
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Potent Multi-Target Inhibition of Cholinesterases and Carbonic Anhydrases by Iridium(III)-Phenanthroline Derivatives: Integrated Structure-Activity Relationship, Molecular Docking and Anticancer Cell Culture Studies.
Köksal Z, Kırboğa KK, Sağır F … +1 more , Şahin Ç
Drug Dev Res · 2026 Apr · PMID 41632019 · Publisher ↗
In this study, a series of novel iridium(III) complexes incorporating 2-phenylimidazo[4,5-f][1,10]phenanthroline ligands with different substituents (methyl (1a), isopropyl (2a), methoxy (3a), phenyl (4a)) were evaluated...
In this study, a series of novel iridium(III) complexes incorporating 2-phenylimidazo[4,5-f][1,10]phenanthroline ligands with different substituents (methyl (1a), isopropyl (2a), methoxy (3a), phenyl (4a)) were evaluated for their in vitro inhibitory activities against anticholinesterase (acetylcholinesterase [AChE], butyrylcholinesterase [BChE]) and carbonic anhydrase [hCA I] and [hCA II]) enzymes. Among the tested compounds, 2a demonstrated exceptional potency with IC values of 66.5 ± 9.06 nM for AChE and 26.45 ± 5.00 nM for BChE, significantly outperforming tacrine. Compound 4a also exhibited strong inhibition of hCA I (IC = 33.0 ± 7.09 nM) and hCA II (IC = 41.79 ± 8.09 nM), surpassing the reference drug acetazolamide. Molecular docking studies revealed that compound 4a exhibited the strongest binding affinity with BChE (PDB: 4BDS) at -12.06 kcal/mol, while compound 2a showed strong binding to hCA II (PDB: 3HS4) at -8.768 kcal/mol. Molecular dynamics simulations over 150 ns confirmed the structural stability of the protein-ligand complexes. Cell viability assays showed that compounds 1a-4a decreased PC3 prostate cancer cell viability in a concentration-dependent manner, with IC values of 10.09, 3.95, 11.39, and 4.51 µM, respectively. This comprehensive study highlights iridium(III) complexes as multitarget therapeutic agents with potent anticholinesterase and carbonic anhydrase inhibitory properties, offering promise for treating neurodegenerative and metabolic disorders.
Antiplasmodial Activity and Pharmacokinetic Profiling of Cryptolepine and 2,7-Dibromocryptolepine With a View to Informing the Design of Novel Antimalarial Cryptolepine Analogues.
Chenu E, Duffy J, Forkuo AD … +5 more , Gbedema SY, Abdelall S, Wahajuddin M, Jones HS, Wright CW
Drug Dev Res · 2026 Apr · PMID 41631973 · Full text
The roots of the climbing shrub Cryptolepis sanguinolenta are traditionally used in West Africa for the treatment of malaria. The principal constituent, cryptolepine (1), has been shown to have antimalarial activity but...
The roots of the climbing shrub Cryptolepis sanguinolenta are traditionally used in West Africa for the treatment of malaria. The principal constituent, cryptolepine (1), has been shown to have antimalarial activity but there are concerns regarding its toxicity on account of its DNA-intercalating property. The synthetic analogue, 2,7-dibromocryptolepine, (2) does not intercalate into DNA and is markedly more active than the parent against Plasmodium sp. in vitro and in vivo. The aim of this study was to carry out a pre-clinical assessment of 1 and 2, and if appropriate, carry out in vivo pharmacokinetic studies. Cryptolepine (1) and 2,7-dibromocryptolepine (2), were evaluated in a range of in vitro assays in line with those recommended by Medicines for Malaria Venture (MMV) for the profiling of a Validated Hit Compound (https://www.mmv.org/frontrunner-templates). In vitro profiling of 1 and 2 showed that 2 is superior to 1 with respect to antiplasmodial activities, and the parasite rate of kill (fast for 2, in contrast with modest for 1); however 2 exhibited potent inhibition of the hERG potassium channel, (IC = 1.0 µM compared with 7.8 µM for 1), raising concerns that 2 may be cardiotoxic, so that 2 was not selected for in vivo pharmacokinetic profiling. The studies of cryptolepine (1) pharmacokinetics in the rat revealed a second peak, especially with oral administration, indicating that enterohepatic circulation following biliary excretion may be taking place. This study complements previous pharmacokinetic data of 1 and presents novel data on 2,7-dibromocryptolepine (2) that will inform the development of cryptolepine analogues as potential antimalarial agents.
Artificial Intelligence in Drug Discovery: Integrative Advances From Data to Therapeutic Innovation.
Mehran MJ, Mohammadzadeh S, Bolideei M … +4 more , Barzigar R, Haider KH, Jadgal N, Bahrami Y
Drug Dev Res · 2026 Apr · PMID 41630488 · Publisher ↗
Integrating artificial intelligence (AI) into drug discovery revolutionizes pharmaceutical research by significantly accelerating the identification, optimization, and development of novel therapeutics. Conventional drug...
Integrating artificial intelligence (AI) into drug discovery revolutionizes pharmaceutical research by significantly accelerating the identification, optimization, and development of novel therapeutics. Conventional drug discovery methods, known for high costs, lengthy timelines, and low success rates, are increasingly being augmented by AI-based technologies, including machine learning (ML), deep learning (DL), and reinforcement learning (RL). These advanced computational approaches enhance key processes, such as target identification, virtual screening, de novo drug design, toxicity prediction, and the optimization of pharmacokinetic and pharmacodynamic profiles, dramatically increasing overall efficiency. AI-driven primary and secondary screening methods improve cell classification, compound prioritization, and drug-target interaction predictions, substantially shortening the progression from preclinical phases to clinical trials. Additionally, AI enables retrosynthesis prediction and reaction yield modeling, optimizing chemical synthesis pathways and reducing the need for resource-intensive experimental procedures. AI's integration into clinical trials has notably improved patient stratification, biomarker discovery, and adaptive trial designs, ultimately delivering more precise and economically feasible therapeutic interventions. Furthermore, AI supports polypharmacological approaches through multitarget drug discovery, drug repurposing (finding new uses for existing drugs), and adverse effect prediction, thereby advancing personalized medicine. Despite these transformative advantages, it's important to note that AI in drug discovery also has limitations, such as ensuring data quality, improving model interpretability, gaining regulatory acceptance, and addressing ethical concerns. This review comprehensively explores the impact of AI throughout the drug discovery pipeline, emphasizing its critical role in expediting the development of life-saving medications and outlining future directions for continued pharmaceutical innovation driven by AI.
Dynorphin A Inhibits the Proliferation, Migration, Invasion, and Stemness of Triple Negative Breast Cancer Cells.
Liu X, Chen B, Dong X … +3 more , Xie C, Liu K, Wu J
Drug Dev Res · 2026 Apr · PMID 41630480 · Publisher ↗
Triple-negative breast cancer (TNBC) is an aggressive subtype that is characterized by a high metastatic capacity, limited therapeutic options, and a poor prognosis, largely because of its stemness properties and aberran...
Triple-negative breast cancer (TNBC) is an aggressive subtype that is characterized by a high metastatic capacity, limited therapeutic options, and a poor prognosis, largely because of its stemness properties and aberrant signaling. Dynorphin A, an endogenous opioid peptide, has been identified as a potential modulator of cancer progression, although its role in TNBC remains unclear. This study demonstrates that the Dynorphin/κ-opioid receptor (KOR) signaling axis is markedly diminished in TNBC patients and TNBC cell lines, suggesting its tumor-suppressive function. Functional assays revealed that Dynorphin A suppresses TNBC cell proliferation, migration, invasion, and stemness while inducing apoptosis. Cell cycle analysis showed Dynorphin A induced G1/S phase arrest. Mechanistically, Dynorphin A blocked epithelial-mesenchymal transition (EMT) by restoring E-cadherin and reducing N-cadherin, Vimentin, and Snail. Morphological analysis confirmed a reversion from mesenchymal to epithelial phenotype. Furthermore, it attenuated stem cell-like properties as indicated by lower levels of CD44, CD133, and Octamer-binding transcription factor 4 (OCT4). Notably, Dynorphin A disrupted zinc finger E-box binding homeobox 1 (ZEB1)-mediated Wnt/β-catenin signaling, and forced expression of ZEB1 partially rescued β-catenin levels, confirming that ZEB1 is a downstream mediator. These findings identify Dynorphin A as a promising endogenous inhibitor of TNBC progression that targets both malignancy and stemness via the ZEB1/β-catenin axis.
Halting Tuberculosis in Its Tracks: Advances and Strategies for Discovering Therapeutic Targets in Mycobacterium tuberculosis.
Sharma A, Singh G, Shrivastava R
Drug Dev Res · 2026 Apr · PMID 41623271 · Publisher ↗
Tuberculosis is a global emergency. Despite two decades of intense research to understand and cure the disease, biological uncertainties prevail and hamper the therapeutic progress. Increasing incidences of multidrug-res...
Tuberculosis is a global emergency. Despite two decades of intense research to understand and cure the disease, biological uncertainties prevail and hamper the therapeutic progress. Increasing incidences of multidrug-resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis strains further complicate tuberculosis control. Modern research, therefore, focuses on development of new antitubercular drugs to treat drug-resistant tuberculosis and shorten the duration of the standard chemotherapy. Fortunately, the recent accelerated approval of delamanid and bedaquiline for use in MDR and XDR tuberculosis has reinvigorated antitubercular research. Although progresses in tuberculosis drug discovery are being made following the availability of M. tuberculosis genome and progressions in molecular biology, novel drug targets and leads are continuously required to strengthen the tuberculosis therapeutic pipeline. Discovery of new targets has eventually promoted tuberculosis therapy, and will keep paving the foundation for generating the future wave of tuberculosis drug leads. This review summarizes important M. tuberculosis drug targets such as F/F ATP synthase, isocitrate lyase, β-ketoacyl-ACP synthases KasA and KasB, QcrB, and mycobactin biosynthesis enzymes MbtA and MbtI, and drugs under preclinical and clinical development stages that aim at making drug discovery breakthroughs. It also discusses the strategies that entail discovery of new mycobacterial therapeutic determinants and provide ideas for development of more efficient drugs. The article comprehensively provides a better understanding of M. tuberculosis drug targets, along with opening new ventures for tuberculosis control and treatment.
Ferroptosis in Cholangiocarcinoma Therapy: Molecular Mechanisms, Pharmacological Modulation and Opportunities for Drug Development.
Athar H, Zulfiqar S, Ali A … +5 more , Armaghan M, Khan K, Setzer WN, Sharifi-Rad J, Calina D
Drug Dev Res · 2026 Apr · PMID 41614243 · Publisher ↗
Cholangiocarcinoma (CCA) is a type of cancer that has a rather high mortality rate and arises from cholangiocytes. Due to its aggressive nature, CCA is considered a rare and highly advanced form of malignancy. This resea...
Cholangiocarcinoma (CCA) is a type of cancer that has a rather high mortality rate and arises from cholangiocytes. Due to its aggressive nature, CCA is considered a rare and highly advanced form of malignancy. This research is detailed around which role does ferroptosis play in CCA and what impact does it have on CCA progression as well as on treatment resistance. A systematic assessment of previously published works was conducted to understand the cellular mechanisms of ferroptosis, the pertinent biological networks, and its possible therapeutic targets. During the research, we discovered that the sensitivity of CCA cells to ferroptosis associated cell death is increased because they have dysregulated iron metabolism and uncontrolled lipid peroxidation. Sensitivity to ferroptosis is regulated by important proteins such as acyl-CoA synthetase long-chain family member 4 (ACSL4) and solute carrier family 7 member 11 (SLC7A11). In addition, the ferroptosis inducers erastin and RSL3 are capable of enhancing the efficacy of traditional therapies and seeking solutions for the chemoresistance problem. The hurdles to be overcome are finding reliable biomarkers for the prediction of ferroptosis sensitivity and designing targeted delivery systems for minimal off-target effects. Clinically, these techniques offer novel concepts in the treatment of CCA, making further research key to these conclusions being adopted in practice.
Reprogramming the Tumor Microenvironment: Calebin A as a Polyphenolic Paradigm Shift in Controlling Inflammation, Stemness, and Resistance in Colorectal Cancer.
Alshehri AA, Khawagi WY
Drug Dev Res · 2026 Apr · PMID 41601391 · Publisher ↗
Colorectal cancer (CRC) remains a leading cause of cancer mortality worldwide, largely due to inflammation-driven progression, cancer stemness, and multidrug resistance (MDR). The tumor microenvironment (TME) orchestrate...
Colorectal cancer (CRC) remains a leading cause of cancer mortality worldwide, largely due to inflammation-driven progression, cancer stemness, and multidrug resistance (MDR). The tumor microenvironment (TME) orchestrates these hallmarks through persistent NF-κB activation and cross-talk among stromal, immune, and cancer cells. This review consolidates mechanistic evidence on Calebin A (CA), a non-curcuminoid polyphenol from Curcuma longa, as a novel multitargeted agent capable of reprogramming the TME and redefining anticancer therapy. A literature integration was conducted across in vitro, ex vivo, and 3D TME models to assess CA's molecular targets, signaling pathways, and pharmacological challenges. CA directly interacts with redox-sensitive cysteine residues in NF-κB (p65) and IKKβ, inhibiting their activation and downstream transcriptional programs. This leads to decreased expression of MMP-9, CXCR4, β1-integrin, and CSC markers (CD44, CD133, ALDH1), along with activation of caspase-3-mediated apoptosis. Moreover, CA reverses MDR by suppressing cytokine-mediated stromal signaling, normalizing redox balance, and enhancing chemosensitivity to 5-FU and cisplatin. Emerging data from other malignancies reveal CA's ability to modulate STAT3, Wnt/β-catenin, and PI3K/Akt pathways, highlighting its universal microenvironmental reprogramming potential. Calebin A represents a polyphenolic paradigm shift in oncology-an agent that restores systemic homeostasis within the TME rather than merely inhibiting oncogenic pathways. Overcoming bioavailability challenges through nanotechnology and combination therapy may accelerate its clinical translation, positioning CA as a prototype for next-generation ecological therapeutics in cancer management. This review consolidates mechanistic evidence on Calebin A (CA), a non-curcuminoid polyphenol from Curcuma longa, as a novel multitargeted agent capable of reprogramming the TME and redefining anticancer therapy. A literature integration was conducted across in vitro, ex vivo, and 3D TME models to assess CA's molecular targets, signaling pathways, and pharmacological challenges. CA directly interacts with redox-sensitive cysteine residues in NF-κB (p65) and IKKβ, inhibiting their activation and downstream transcriptional programs. This leads to decreased expression of MMP-9, CXCR4, β1-integrin, and CSC markers (CD44, CD133, ALDH1), along with activation of caspase-3-mediated apoptosis. Moreover, CA reverses MDR by suppressing cytokine-mediated stromal signaling, normalizing redox balance, and enhancing chemosensitivity to 5-FU and cisplatin. Emerging data from other malignancies reveal CA's ability to modulate STAT3, Wnt/β-catenin, and PI3K/Akt pathways, highlighting its universal microenvironmental reprogramming potential. Calebin A represents a polyphenolic paradigm shift in oncology-an agent that restores systemic homeostasis within the TME rather than merely inhibiting oncogenic pathways. Overcoming bioavailability challenges through nanotechnology and combination therapy may accelerate its clinical translation, positioning CA as a prototype for next-generation ecological therapeutics in cancer management.
From Cancer to Neuroprotection: Pazopanib Modulates the RIPK1/RIPK3/MLKL and PGAM5/DRP1 Pathways in 3- Nitropropionic Acid-Induced Huntington's Disease.
Eltarzy MA, Rabie MA, Sayed RH … +2 more , Ahmed MAE, Ahmedy OA
Drug Dev Res · 2026 Apr · PMID 41591821 · Publisher ↗
Huntington's disease (HD) is a progressive neurodegenerative disorder with a poorly understood neurobiological basis. Among the various forms of programmed cell death implicated in neurodegeneration, necroptosis has rece...
Huntington's disease (HD) is a progressive neurodegenerative disorder with a poorly understood neurobiological basis. Among the various forms of programmed cell death implicated in neurodegeneration, necroptosis has recently garnered significant attention. Notably, dysregulated necroptosis provokes immune response that drives excessive pro-inflammatory cytokine production, promoting further necroptotic cell death through TNF-α/RIPK1 signaling. Consequently, necroptosis exacerbates neuroinflammation, contributing to the progression of different neurodegenerative diseases. However, the precise role of necroptosis in HD pathogenesis remains unclear. Given the growing interest in repurposing FDA-approved drugs for novel therapeutic interventions, this study investigates the anti-cancer agent Pazopanib (Pazo) as a potential neuroprotective approach for HD. This study assesses Pazo's ability to mitigate necroptosis by targeting the RIPK1/RIPK3/MLKL pathway in a model of HD produced by 3-nitropropionic acid (3-NP). Sixty male Wistar rats were randomly assigned to four groups: Group I received normal saline; Group II received Pazo (15 mg/kg, i.p.); Group III received 3-NP (10 mg/kg, i.p.); and Group IV received 3-NP (10 mg/kg, i.p.) and Pazo (15 mg/kg, i.p.). Behavioral assessments, including open field, rotarod, and wire hanging tests, demonstrated that Pazo significantly improved motor function. At the molecular level, Pazo inhibited PGAM5, a key regulator of mitochondrial fission, effectively reversing the RIPK1/RIPK3/MLKL necroptotic cascade and the consequent immune activation. This suppression of necroptosis was associated with reduced microgliosis, neuroinflammation and enhanced neuronal survival within the striatum. These findings highlight the potential of Pazo as a neuroprotective agent against HD by leveraging its antioxidant, anti-inflammatory, immune-modulating, and anti-necroptotic properties.
Thioxo-Based Kojic Acid Derivatives as Potent Tyrosinase Inhibitors With Antitubercular and Antidermatophytic Potential.
Karakaya G, Sari S, Deniz FSS … +3 more , Özçelik B, Orhan IE, Aytemir MD
Drug Dev Res · 2026 Apr · PMID 41591809 · Publisher ↗
A novel series of sulfur-containing analogs derived from the 3-hydroxy-6-methyl-2-((4-phenylpiperazin-1-yl)methyl)-4H-pyran scaffold was synthesized. Spectroscopic techniques and elemental analysis confirmed their struct...
A novel series of sulfur-containing analogs derived from the 3-hydroxy-6-methyl-2-((4-phenylpiperazin-1-yl)methyl)-4H-pyran scaffold was synthesized. Spectroscopic techniques and elemental analysis confirmed their structures. The biological potential of these compounds, along with their previously reported bioisosteres, was assessed as tyrosinase inhibitors, as well as antitubercular and antidermatophytic agents. In all derivatives where the carbonyl group is converted to a thiocarbonyl group, tyrosinase inhibition increases significantly, with the most effective compounds being identified as compounds 6c and 6d, which carry the 4-fluoro and 4-nitro groups, with IC values of 0.143 and 0.121 mg/mL, respectively, compared with kojic acid (0.067 mg/mL). Molecular modeling predicted enhanced engagement with the copper ions in tyrosinase active site upon shifting from carbonyl to thiocarbonyl. Similarly, all thioxo-based analogs (6a-d) demonstrated antimycobacterial activity comparable to that of the reference drug ethambutol, particularly against Mycobacterium avium. These compounds also showed pronounced antidermatophytic activity, with MIC values ranging from 1 to 2 μg/mL against Trichophyton mentagrophytes var. erinacei, Epidermophyton floccosum, and Microsporum gypseum. Cytotoxicity assays in HeLa and MRC-5 cell lines revealed that the compounds remained bioactive at non-toxic concentrations ( ≥ 128 μg/mL). Overall, the replacement of the carbonyl group with a thioxo functionality markedly enhanced the bioactivity of the derivatives predictably through improved tyrosinase inhibition, highlighting their potential as promising lead scaffolds for the future development of multifunctional therapeutic agents.
Discovery of Bufalin as a Molecular Glue Degrader of NCAPG to Inhibit the Proliferation of Hepatoma Cells.
Wu C, Zhuo X, Yang J … +8 more , Tang Y, Wang W, Wu M, Miao G, Li C, Shen H, Qian J, Wang D
Drug Dev Res · 2026 Apr · PMID 41586569 · Publisher ↗
Inhibiting the malignant proliferation is crucial for managing the cancer progression. NCAPG (Non-SMC condensin I complex subunit G) is a main component in cell proliferation, which is highly expressed in liver tumors an...
Inhibiting the malignant proliferation is crucial for managing the cancer progression. NCAPG (Non-SMC condensin I complex subunit G) is a main component in cell proliferation, which is highly expressed in liver tumors and negatively correlated with the overall survival of hepatocellular carcinoma (HCC) patients. In this study, we identified bufalin as a molecular glue for the first time that specifically degraded NCAPG by coupling it to cathepsin V (CTSV). Distinguished from traditional PROTACs, bufalin served as a molecular glue with the distinct advantages of a smaller molecular weight and superior bioavailability. This degradation inhibited the proliferation of HCC cells by inducing G2/M phase cell cycle arrest at low doses (20-40 nM), but did not trigger the apoptosis signaling. Using co-immunoprecipitation and confocal microscopy, we confirmed the interaction between CTSV and NCAPG by bufalin. Knockdown of CTSV or NCAPG attenuated the anti-proliferation effects of bufalin in HCC cells. Cell cycle analysis also showed significantly reduced G2/M arrest in knockdown cells. The downstream proliferation regulators Cyclin D1 and CDK1 were also regulated by bufalin in a CTSV/NCAPG-dependent manner. Our study not only identified the CTSV-NCAPG complex as a novel therapeutic target but also discovered a potential molecular glue, bufalin, which exerts anti-proliferation effects through cell cycle regulation. These findings highlight the potential clinical translational value of bufalin as a promising, bioavailable therapeutic agent for the targeted treatment of liver cancer.
TNFRSF17 Knockdown Alleviates Mitochondrial Dysfunction and Inflammation in COPD Through Suppression of the JAK2/STAT3 Pathway.
Yang X, Huang Y, Zheng A … +2 more , Mu H, Cui J
Drug Dev Res · 2026 Apr · PMID 41586567 · Publisher ↗
Mitochondrial dysfunction is a hallmark of chronic obstructive pulmonary disease (COPD). Nevertheless, the precise molecular mechanisms of COPD have yet to be fully elucidated. Protein-protein interaction (PPI) network c...
Mitochondrial dysfunction is a hallmark of chronic obstructive pulmonary disease (COPD). Nevertheless, the precise molecular mechanisms of COPD have yet to be fully elucidated. Protein-protein interaction (PPI) network construction and weighted gene co-expression network analysis (WGCNA) were conducted to identify hub genes related to mitochondrial homeostasis. A TNF receptor superfamily member 17 (TNFRSF17)-knockdown model was established in human bronchial epithelial (HBE) cells treated with cigarette smoke extract (CSE), and in mice exposed to CS and lipopolysaccharide (LPS). Cell counting kit-8, enzyme-linked immunosorbent assay, flow cytometry, JC-1 staining, senescence-associated β-galactosidase staining, western blot analysis, and hematoxylin-eosin staining were used to evaluate cellular function, inflammation, and pathology. The involvement of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway was investigated using colivelin analog 1 (C-A1). CD19, POU2AF1, FCRLA, and TNFRSF17 were identified as mitochondrial homeostasis-related hub genes, all of which were upregulated in COPD. Following TNFRSF17 knockdown, COPD mice exhibited reduced alveolar destruction, inflammatory cell infiltration, and collagen deposition. TNFRSF17 knockdown alleviated CS-induced mitochondrial membrane depolarization, calcium overload, reactive oxygen species (ROS) accumulation, ATP depletion, IL-6 and TNF-α secretion, and cellular senescence both in vitro and in vivo. TNFRSF17 knockdown suppressed the phosphorylation of JAK2 and STAT3. The protective effects mediated by TNFRSF17 knockdown were significantly abrogated by the C-A1 treatment. TNFRSF17 knockdown inhibits mitochondrial dysfunction, inflammation, and senescence in COPD by obstructing the JAK2/STAT3 pathway, offering a promising therapeutic strategy for COPD.
Targeting of PCSK9 in the Management of Alzheimer's Disease: Expanding the New Potential Key Player.
Alanazi M, Al-Kuraishy HM, Hussain NR … +5 more , Waheed HJ, Al-Gareeb AI, Albuhadily AK, Waheeb TS, Batiha GE
Drug Dev Res · 2026 Apr · PMID 41549952 · Publisher ↗
Alzheimer's disease (AD) represents the most common cause of dementia in the elderly population worldwide. However, most of the anti-AD medications did not resolve the underlying neuropathology. Consequently, targeting o...
Alzheimer's disease (AD) represents the most common cause of dementia in the elderly population worldwide. However, most of the anti-AD medications did not resolve the underlying neuropathology. Consequently, targeting other signaling pathways may be helpful in the management of AD. Particularly, preprotein convertase subtilisin/kexin type 9 (PCSK9), which is a regulator protein of low-density lipoprotein (LDL), is intricate in the pathogenesis of AD. Normally expressed PCSK9 in the brain plays a critical role in the regulation of neuronal differentiation and apoptosis, and degradation of LDL receptors (LDLRs). However, exaggerated brain PCSK9 via induction of inflammation and oxidative stress and related neurodegeneration may induce AD development. Therefore, neuronal PCSK9 has dual role in the CNS. Nevertheless, the exact role of PCSK9 in AD neuropathology is still elusive. Therefore, in the review, we try to revise and discuss the potential role of PCSK9 in the pathogenesis of AD, and how targeting of this protein may be helpful in the management of AD.
Potential and Applications of Mn Complexes in Breast Cancer.
Guo J, Yang T, Li D … +2 more , Ma Y, Man X
Drug Dev Res · 2026 Apr · PMID 41549942 · Publisher ↗
Breast cancer remains one of the leading causes of mortality among women worldwide, and triple-negative breast cancer continues to show poor clinical outcomes due to the absence of actionable targets. As platinum-based t...
Breast cancer remains one of the leading causes of mortality among women worldwide, and triple-negative breast cancer continues to show poor clinical outcomes due to the absence of actionable targets. As platinum-based therapies face well-recognized limitations related to toxicity, resistance, and restricted mechanisms of action, manganese (Mn) complexes have recently attracted interest as non-platinum metallodrugs with multimodal antitumor activity, including DNA interaction, Fenton-like ROS generation, and immunomodulation such as activation of the cGAS-STING pathway. This narrative review summarizes studies identified through PubMed and Web of Science searches up to April 2025 and integrates current progress on Mn complexes in breast cancer, including their cytotoxic effects, immune-related functions, and emerging theranostic applications. Representative complexes are compared in terms of structure, activity, and early structure-activity features. At the same time, key translational challenges-including solubility, kinetic and redox stability, bioavailability, and Mn-specific toxicity such as neurotoxicity-are highlighted alongside the limited pharmacokinetic and safety data currently available. Overall, this review outlines both the therapeutic potential and the practical limitations of Mn complexes and identifies research priorities needed to advance these agents toward meaningful clinical translation in breast cancer.
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