Drug Development Research[JOURNAL]
Sun
200 papers
Blueprint for Drug Repurposing Success: Foundational Concepts and Practical Framework.
Ray A, Dey S, Sur D
Drug Dev Res · 2026 Apr · PMID 41904819 · Publisher ↗
Drug repurposing involves identifying new therapeutic applications for existing clinically evaluated compounds. In contrast to conventional drug development, which typically spans over a decade and demands substantial fi...
Drug repurposing involves identifying new therapeutic applications for existing clinically evaluated compounds. In contrast to conventional drug development, which typically spans over a decade and demands substantial financial investment, repurposed drugs can achieve regulatory approval in approximately half the time and cost by capitalizing on their established pharmacokinetic, safety, and clinical profiles. This review provides a comprehensive analysis of the traditional and computational strategies employed in drug repurposing. Experimental methodologies include binding affinity assays, clinical data mining and phenotype-based screening. Computational approaches are categorized into structure-based, signature-based, pathway-based, knowledge-based, and target-based strategies. The recent integration of artificial intelligence (AI) and machine learning (ML) within repurposing pipelines is also examined, emphasizing their ability to efficiently process large-scale datasets, improve the predictive accuracy of drug-target interactions, and support the advancement of repurposing efforts. Furthermore, this review systematically compares prominent computational platforms, virtual screening tools, and bioinformatics resources, highlighting their respective strengths and limitations. Emerging AI-driven models, such as deep learning architectures, graph neural networks, knowledge graphs, and network pharmacology frameworks, have transformative roles in broadening the scope of drug repurposing. This comprehensive review is intended to assist medicinal chemists, computational biologists, and drug discovery scientists in expediting research efforts by effectively utilizing existing resources for repurposing-driven innovations.
Synthesis, Characterization, and Biological Evaluation of Aliphatic-Substituted Benzimidazole Derivatives: Induction of Apoptosis, Cell Cycle Arrest, and Molecular Docking in Breast Cancer Cells.
Keser M, Çamlı Pulat Ç, Atmaca H … +5 more , Akgün H, Albay C, Menteşe E, Bektaş H, Ilhan S
Drug Dev Res · 2026 Apr · PMID 41904818 · Full text
A new series of aliphatic-substituted benzimidazole derivatives was synthesized and structurally characterized to evaluate their potential anticancer activity. Among the synthesized compounds, compound 4 exhibited the mo...
A new series of aliphatic-substituted benzimidazole derivatives was synthesized and structurally characterized to evaluate their potential anticancer activity. Among the synthesized compounds, compound 4 exhibited the most potent cytotoxic effects against MCF-7 and MDA-MB-231 breast cancer cell lines, with IC₅₀ values comparable to those of cisplatin, while displaying lower toxicity toward normal breast epithelial cells (MCF-10A). Flow cytometric analysis revealed that treatment with compound 4 resulted in significant accumulation of cells in the S phase, indicating inhibition of DNA synthesis and replication. Furthermore, Annexin V/PI double-staining analysis demonstrated a marked increase in both early and late apoptotic cell populations, confirming the activation of apoptotic pathways. Molecular docking studies supported these experimental findings by revealing strong interactions of compound 4 with key regulatory proteins involved in apoptosis and cell cycle progression, including Bcl-2, Bcl-xL, CDK2, and Cyclin E. The compound exhibited the highest binding affinity toward CDK2 (-164.055 kcal/mol), forming hydrogen bonds with critical residues (LEU134, ASP145, GLN131, and LYS33) within the ATP-binding pocket, suggesting potential inhibition of kinase activity. Interactions with Bcl-2 and Bcl-xL occurred within the BH3-binding grooves, which may impair their anti-apoptotic functions and promote mitochondrial-mediated apoptosis. Collectively, the in vitro and in silico results indicate that this newly synthesized benzimidazole derivative exerts its anticancer effects through a dual mechanism involving cell cycle arrest and apoptosis induction. The selective cytotoxicity and multitarget interaction profile of compound 4 highlight its potential as a promising lead compound for the development of novel therapeutic agents against breast cancer.
PTC-Assisted Chemoselective S-Alkylation of 5-Mercapto-1,3,4-Oxadiazol Derivative: Multi-Target Anticancer via EGFR, Telomerase, and Thymidylate Synthase Inhibition With Apoptosis Induction.
Zakaria A, Al-Karmalawy AA, Hawas SS … +4 more , Ali AK, Elsayed GA, Khatib AOA, Abbass EM
Drug Dev Res · 2026 Apr · PMID 41904811 · Publisher ↗
Multi-target enzyme inhibition represents a promising strategy to overcome resistance and improve therapeutic outcomes in cancer therapy. In this study, a new series of 1,3,4-oxadiazole derivatives was synthesized and ev...
Multi-target enzyme inhibition represents a promising strategy to overcome resistance and improve therapeutic outcomes in cancer therapy. In this study, a new series of 1,3,4-oxadiazole derivatives was synthesized and evaluated for cytotoxic and multi-target anticancer activities. Several compounds demonstrated potent antiproliferative effects against HepG2, MCF-7, and HCT-116 cancer cell lines with reduced toxicity toward WI-38 normal fibroblasts. Among them, compounds 1, 9, 12, and 13 emerged as the most promising candidates, showing strong cytotoxicity and favorable selectivity profiles. Enzyme inhibition assays confirmed their ability to target key oncogenic enzymes, including wild-type and mutant (T790M) EGFR, telomerase, and thymidylate synthase. Mechanistic studies revealed that compound 12 induced G1 phase cell cycle arrest and promoted apoptosis in HepG2 cells with minimal necrosis. Molecular docking, molecular dynamics simulations, and MM-GBSA analyses supported stable binding of the active compounds within the catalytic sites of the investigated enzymes. Overall, these findings identify compounds 1, 9, 12, and 13 as promising multi-target anticancer leads warranting further optimization and development.
Heteromerization, Biased Agonism, and Allosteric Modulation of G Protein-Coupled Receptors in Addiction: Mechanistic Insights and Therapeutic Implications.
Alhosaini KA, Alanazi MM, Alsulaihim IN … +3 more , Alonazi AS, Alasmari FF, Khan MR
Drug Dev Res · 2026 Apr · PMID 41904810 · Publisher ↗
G protein-coupled receptors (GPCRs) are core transducers of psychoactive drug action, shaping second messenger signaling, ion channel function, and neurotransmitter release in reward- and stress-related circuits. Despite...
G protein-coupled receptors (GPCRs) are core transducers of psychoactive drug action, shaping second messenger signaling, ion channel function, and neurotransmitter release in reward- and stress-related circuits. Despite decades of therapeutic targeting, GPCR-based strategies for substance use disorders have delivered uneven clinical benefit, in part because in vivo receptor signaling is strongly shaped by receptor context, circuit state, and exposure history. This narrative review focuses on three mechanistic routes to therapeutic selectivity: (i) GPCR heteromerization, (ii) biased agonism, and (iii) allosteric modulation. We synthesize evidence across dopaminergic, opioid, cannabinoid, and group II metabotropic glutamate receptor systems, selected because they are central to mesocorticolimbic function and because they provide the strongest current case studies for these selectivity mechanisms. For receptor heteromers, we apply an evidence-graded interpretation that distinguishes proximity-based findings from native-tissue signatures and from in vivo functional validation. For μ-opioid receptor biased agonism, we critically reassess the preclinical rationale and the clinical experience with proposed "G protein-biased" ligands, emphasizing how assay amplification, intrinsic efficacy, and endpoint choice can confound bias claims and limit safety translation. For allosteric modulation, we highlight the relapse-relevant preclinical evidence for mGlu2/3 positive allosteric modulators and discuss predictable hurdles including probe dependence, species differences, and durability of benefit. Across these themes, the central translational message is that single-receptor, single-pathway models are often insufficient; progress is most likely when mechanistic claims are matched to evidence strength and when target engagement is linked to circuit-level outcomes and clinically meaningful endpoints. Future advances will depend on integrating structure-informed pharmacology with in vivo biomarkers, standardized relapse outcomes, and longer-term trials, alongside careful safety evaluation and equitable access to effective treatments.
FGF18 Ameliorates HIV-1 Tat-Induced Blood-Brain Barrier Disruption via Wnt/β-Catenin Signaling.
Zhang P, Wei S, Fu F … +2 more , Gu H, Yang Y
Drug Dev Res · 2026 Apr · PMID 41902332 · Publisher ↗
Dysregulated expression of tight junction proteins and compromise of blood-brain barrier (BBB) integrity are associated with pathological progression of HIV-1-associated neurocognitive disorders (HAND). Fibroblast growth...
Dysregulated expression of tight junction proteins and compromise of blood-brain barrier (BBB) integrity are associated with pathological progression of HIV-1-associated neurocognitive disorders (HAND). Fibroblast growth factor-18 (FGF18), an important member of the fibroblast growth factor (FGF) family, has been considered a neuroprotectant with a wide range of physiological functions. However, the effects of FGF18 in HAND have not been reported previously. Here, we report that FGF18 expression was reduced in the cortex of mice challenged with HIV-1 Tat. Intracerebroventricular administration of FGF18 suppressed vascular inflammation in the cortex of HIV-1 Tat-challenged mice by inhibiting VCAM-1 and ICAM-1 expression. FGF18 alleviated BBB dysfunction induced by HIV-1 Tat through upregulating ZO-1 expression. Mechanistically, FGF18 prevented HIV-1 Tat-induced downregulation of Wnt-3a and β-catenin. We further demonstrate that FGF18 ameliorated HIV-1 Tat-induced cytotoxicity in bEnd.3 brain microvascular endothelial cells by reducing LDH and HMGB-1 release. Moreover, FGF18 protected the endothelial permeability of bEnd.3 cells and restored trans-endothelial electrical resistance (TEER) in cells challenged with HIV-1 Tat. Consistently, FGF18 prevented the reduction of ZO-1 expression as well as Wnt-3a/β-catenin levels in bEnd.3 cells challenged with HIV-1 Tat. Importantly, silencing of Wnt-3a abrogated the beneficial effects of FGF18 in increasing ZO-1 expression and reducing endothelial permeability, indicating that the protective effects of FGF18 are mediated by Wnt-3a/β-catenin signaling. We conclude that FGF18 may serve as an effective neuroprotective agent for the treatment of HAND.
TRIM47 Promotes Atherosclerosis by Activating NF-κB Signaling via IκBα Ubiquitination.
Qin X, Luo J, Yuan Y … +5 more , Liu B, Zhang X, Zhang Y, Fang Y, Wei Y
Drug Dev Res · 2026 Apr · PMID 41902331 · Publisher ↗
Atherosclerosis, a major contributor to cardiovascular diseases, is characterized by chronic inflammation in arterial walls. The role of NF-κB signaling in this process is well-established, but the upstream regulators re...
Atherosclerosis, a major contributor to cardiovascular diseases, is characterized by chronic inflammation in arterial walls. The role of NF-κB signaling in this process is well-established, but the upstream regulators remain incompletely understood. This study explored the role of TRIM47, an E3 ubiquitin ligase, in promoting atherosclerosis through NF-κB activation. In vitro studies used human umbilical vein endothelial cells (EC) treated with oxidized low-density lipoprotein (ox-LDL). TRIM47 expression was modulated using siRNA knockdown and overexpression plasmids. Inflammation markers, cell viability, and NF-κB activation were assessed. In vivo studies utilized ApoE-/- mice fed a high-fat diet and treated with adenovirus-mediated TRIM47 knockdown. ox-LDL treatment increased TRIM47 expression in EC, alongside elevated inflammatory markers, and reduced cell viability. TRIM47 overexpression exacerbated ox-LDL-induced inflammation, while knockdown attenuated these effects. Mechanistically, TRIM47 directly interacted with IκBα, promoting its ubiquitination and degradation, leading to enhanced NF-κB activation. In ApoE-/- mice, TRIM47 knockdown significantly reduced atherosclerotic plaque formation and lesion size. This study identified TRIM47 as a novel regulator of atherosclerosis progression through IκBα ubiquitination and NF-κB activation. TRIM47 knockdown attenuated vascular inflammation and atherosclerotic plaque formation. The findings suggested that TRIM47 might be a potential therapeutic target for the treatment of atherosclerosis and related cardiovascular diseases.
Hexahydroquinoline Featuring Amide Functionality: A Promising Scaffold With Calcium Channel Blocking Activity.
Koçak Aslan E, Lam K, Huang S … +11 more , Coşkun GP, Karagüzel A, Denzinger K, Birgül K, Ülgen M, Nafie JW, Şahin O, Armstrong DW, Zamponi GW, Wolber G, Gündüz MG
Drug Dev Res · 2026 Apr · PMID 41832946 · Full text
Hexahydroquinoline (HHQ) is a widely recognized scaffold that has garnered considerable attention owing to its diverse pharmacological properties. The structure of HHQ includes a 1,4-dihydropyridine (DHP) ring, which ser...
Hexahydroquinoline (HHQ) is a widely recognized scaffold that has garnered considerable attention owing to its diverse pharmacological properties. The structure of HHQ includes a 1,4-dihydropyridine (DHP) ring, which serves as the pharmacophore for the predominant class of drugs known as calcium channel blockers. DHPs are frequently utilized in the management of cardiovascular diseases and also show potential for pain management. Since all DHPs on the market possess ester functionality, we aimed to employ bioisosteric replacement to observe if their amide-containing counterparts would still block calcium channels. Therefore, we synthesized new HHQs with ester or amide functionality (EM1-EM15) and investigated their effects on L-(Ca1.2) and T-(Ca3.2)-type calcium channels using the whole-cell patch clamp technique. Although the amide derivatives were somewhat less effective than their ester counterparts, they still blocked calcium channels to a significant degree. Retesting EM4 enantiomers on two types of calcium channels demonstrated that the (R)-isomer was more responsible for the blocking activity in both cases. Molecular docking and molecular dynamics simulations demonstrated that (R)-EM4 and (R)-EM6 adopt binding modes in Ca1.2 similar to amlodipine, while showing favorable stability. Docking studies in Ca3.2 suggested that EM compounds bind within the Ⅲ-Ⅳ fenestration, a reported non-selective DHP binding site. Furthermore, amide derivatives were found to be more metabolically stable based on the in vitro experiments conducted on rat microsomes. Overall, our study reveals HHQ with an amide group as a promising new scaffold for developing future calcium channel blockers for treating cardiovascular and pain conditions.
Structure-Guided Optimization and Biological Validation of 1,3,4-Thiadiazole-Based SIRT2 Inhibitors Reinforcing Channel Entrance Interactions.
Aksel AB, Ozgencil F, Bakar-Ates F … +7 more , Gunindi HB, Massarotti A, Ozkan E, Kaya SG, Gozelle M, Ozkan Y, Eren G
Drug Dev Res · 2026 Apr · PMID 41805109 · Full text
SIRT2, the cytoplasmic member of the sirtuin family, is generally acknowledged to promote cancer and contribute to the progression of various pathologies, including neurodegeneration, inflammation, obesity, and bacterial...
SIRT2, the cytoplasmic member of the sirtuin family, is generally acknowledged to promote cancer and contribute to the progression of various pathologies, including neurodegeneration, inflammation, obesity, and bacterial infection through the deacetylation of target substrates. In our previous efforts we identified potent and highly selective SIRT2 inhibitors with IC values in the micromolar range. To further optimize their activity, we performed molecular docking-guided design and subsequent synthesis of a series of novel 1,3,4-thiadiazole derivatives. SIRT inhibitory screening identified that ST131 and ST132 achieved moderate inhibitory effects against SIRT2 with IC values of 8.95 and 6.62 µM, respectively. Moreover, cellular assays in MCF-7 breast cancer cells revealed that ST132 has shown an antiproliferative effect, as well as increased acetylated α-tubulin expression levels, which is typically consistent with SIRT2 inhibition. In addition, docking studies were performed to analyze and rationalize the structural differences responsible for SIRT2 activity, shedding light on the importance of the interactions occurring at the entrance of the binding site. Finally, molecular mechanics-generalized born surface area (MM-GBSA) and molecular dynamics (MD) simulation approaches were conducted to verify the stability of ST132 in the complex with SIRT2.
Ceritinib Induces Mitochondrial Fragmentation in Thyroid Cancer Cells by Targeting Drp-1.
Qin D, Ding W, Wu X … +4 more , Peng C, Bo Y, Wang D, Qin Y
Drug Dev Res · 2026 Apr · PMID 41805100 · Publisher ↗
Mitochondrial dynamics play a crucial role in thyroid cancer progression by regulating apoptosis, metabolism, and oxidative stress. Ceritinib, a tyrosine kinase inhibitor, shows potential anticancer effects; however, its...
Mitochondrial dynamics play a crucial role in thyroid cancer progression by regulating apoptosis, metabolism, and oxidative stress. Ceritinib, a tyrosine kinase inhibitor, shows potential anticancer effects; however, its impact on mitochondrial function in thyroid cancer remains obscure. Herein, we aim to investigate the impact of ceritinib on the mitochondrial functionality in TPC-1 thyroid carcinoma cells and the underlying mechanism. Cell viability was assessed with the CCK-8 assay, and the cytotoxicity was determined by evaluation of the lactate dehydrogenase (LDH) release assay. Mitochondrial reactive oxygen species (ROS) were detected by MitoSOX Green staining. Enzyme-linked immunosorbent assay (ELISA) was applied for 8-hydroxydeoxyguanosine (8-OHdG) determination. Real-time PCR was employed for mRNA levels assessment, and western blotting was applied for protein levels. The morphology of mitochondria was evaluated by means of Mitotracker Red CMXRos staining. Ceritinib triggered mitochondrial oxidative stress, evidenced by elevated ROS and 8-OHdG levels, while suppressing manganese superoxide dismutase (Mn-SOD) activity. It also impaired mitochondrial respiration, ATP production, and Complex III activity, leading to dysfunction. Notably, ceritinib promoted mitochondrial fragmentation by enhancing dynamin-related protein 1 (Drp1) translocation to mitochondria, reducing l-OPA1 and increasing S-OPA1 levels, without altering mitofusins 1 and 2 (Mfn-1 and -2) expression. Mechanistically, ceritinib activated the Mitochondrial Calcium Uniporter (MCU)/calpain pathway, increasing MCU, calpain1/2, and calpain activity. Inhibition of MCU by RU360 reversed ceritinib-induced Drp1 mitochondrial translocation, fragmentation, and ATP depletion. Our findings reveal that ceritinib disrupts mitochondrial dynamics via the MCU/calpain/Drp1 axis. This study identifies a previously unreported mechanism for ceritinib in thyroid carcinoma, suggesting a novel therapeutic strategy.
Zeylenone Attenuates Tamoxifen Resistance by Directly Binding to CTCF and Inhibiting the CTCF-CENPK-JAK1/STAT3 Signaling Axis in Breast Cancer.
Li G, Deng Z, Zhang W … +2 more , Ge P, Wang K
Drug Dev Res · 2026 Apr · PMID 41797275 · Publisher ↗
This study was designed to investigate the effects of zeylonone (Zey) on attenuating tamoxifen (TAM) resistance in breast cancer cells in vitro and in vivo and its underlying mechanisms. Database analysis and clinical sa...
This study was designed to investigate the effects of zeylonone (Zey) on attenuating tamoxifen (TAM) resistance in breast cancer cells in vitro and in vivo and its underlying mechanisms. Database analysis and clinical sample validation revealed that CENPK is significantly upregulated in breast cancer tissues and TAM-resistant cells, and its expression positively correlates with CTCF mRNA levels. Knockdown of CENPK markedly suppressed proliferation and colony formation, induced G0/G1 cell cycle arrest, promoted apoptosis in MCF-7/TAM cells, and inhibited tumor growth in nude mice, thereby attenuating TAM resistance. Zey treatment resulted in dose- and time-dependent downregulation of both CTCF and CENPK at the protein and mRNA levels. Molecular docking provided preliminary computational evidence suggesting Zey can bind to CTCF (binding energy:-6.9 kcal/mol), with subsequent biophysical and functional assays supporting this interaction, and thermal shift assays demonstrated that Zey enhances the thermal stability of CTCF. ChIP-qPCR and luciferase reporter assays confirmed that CTCF directly binds to the CENPK promoter and positively regulates its transcription, and Zey inhibits this regulatory process by directly binding to CTCF. Mechanistically, the CTCF/CENPK axis is associated with JAK1/STAT3 pathway modulation (increasing phosphorylation levels of JAK1 and STAT3), and Zey significantly reduces pathway activity by suppressing this axis. Overexpression of CTCF attenuated the anti-resistance effects of Zey, whereas knockdown of CENPK or JAK1 restored Zey's efficacy. While CTCF and CENPK have been individually implicated in cancer progression, this study provides the first evidence linking them in a functional regulatory axis that drives tamoxifen resistance. Zey attenuates tamoxifen resistance in breast cancer cells by directly binding to CTCF, thereby inhibiting CTCF-mediated transcriptional regulation of CENPK, downregulating CENPK expression, and subsequently suppressing the JAK1/STAT3 signaling pathway.
Pyrrolidine Derivatives in Modern Drug Discovery: Emerging Structure Activity Relationships and Dual Antidiabetic-Anticancer Potential.
Bhat AA, Ahmed M, Elboughdiri N … +8 more , Thakur P, Natarajan V, El-Kott AF, Rajab BS, Alghamdi S, Singh J, Wani AK, Hameed A
Drug Dev Res · 2026 Apr · PMID 41797273 · Publisher ↗
Pyrrolidine, a five-membered nitrogen-containing heterocycle, has emerged as an important structural motif in medicinal chemistry owing to its pronounced pharmacological versatility, conformational flexibility, and favor...
Pyrrolidine, a five-membered nitrogen-containing heterocycle, has emerged as an important structural motif in medicinal chemistry owing to its pronounced pharmacological versatility, conformational flexibility, and favorable physicochemical properties. In recent years, pyrrolidine-based compounds have attracted considerable attention for their therapeutic potential in the management of diabetes and cancer, two major global health challenges. This review compiles and critically analyzes recent advances in the design, synthesis, and biological evaluation of pyrrolidine derivatives exhibiting antidiabetic and anticancer activities. Particular emphasis is placed on structure-activity relationship (SAR) studies, highlighting how subtle modifications in substitution patterns, electronic properties, and steric factors markedly influence biological performance. Numerous studies demonstrate that strategic functionalization at key positions of the pyrrolidine ring leads to enhanced selectivity, improved inhibition of carbohydrate-metabolizing enzymes (including α-glucosidase, α-amylase, and DPP-IV), and pronounced antiproliferative effects against a range of cancer cell lines. By integrating important findings reported over the past decade (2013-2025), this review underscores the potential of pyrrolidine derivatives as dual-action therapeutic agents and provides a coherent framework to guide the rational design of future drug candidates.
Exploring Pyrazolo[3,4-b]Pyridine and Spiro-Oxindole Hybrids as Selective CDK2 or EGFR Inhibitors for Targeted Cancer Therapy: Design, Synthesis, and Molecular Modeling Insights.
Farouk AKBAW, Al-Tanany AAA, Elnagar MR … +5 more , Tawfik MM, El-Ashrey MK, Abbas SE, Abdel-Aziz HA, Ezzat MAF
Drug Dev Res · 2026 Apr · PMID 41797262 · Publisher ↗
A new series of pyrazolo[3,4-b]pyridine and spiro-oxindole derivatives were rationally designed, synthesized, and biologically assessed as either CDK2 or EGFR inhibitors with potential anticancer activity. The CDK2 inhib...
A new series of pyrazolo[3,4-b]pyridine and spiro-oxindole derivatives were rationally designed, synthesized, and biologically assessed as either CDK2 or EGFR inhibitors with potential anticancer activity. The CDK2 inhibitory evaluation of pyrazolo[3,4-b]pyridines 6a-g and 7a-f revealed that compounds 6e, 7b, and 7c exhibited potent inhibition (IC₅₀ = 0.88, 1.89, and 1.23 μM, respectively), compared to roscovitine (IC₅₀ = 0.84 μM). Among the spiro-oxindole derivatives 8a-d, compounds 8b and 8c demonstrated remarkable EGFR inhibition (IC₅₀ = 0.13 and 0.09 μM, respectively) and significant activity against mutant EGFR (IC₅₀ = 0.32 and 0.14 μM) relative to gefitinib (IC₅₀ = 0.03 and 0.18 μM, respectively). Furthermore, compounds 6e and 8c exhibited selective cytotoxicity versus MCF-7 and MDA-MB231 cancer cells, respectively, with negligible cytotoxic effects on normal Vero cells. Flow cytometric analysis confirmed that compounds 6e and 8c induced G1-phase cell cycle arrest and apoptosis in MCF-7 and MDA-MB-231, respectively, accompanied by a pronounced increase in the Bax/Bcl-2 ratio, with values of 12.15 and 16.93 fold, respectively. Molecular docking studies combined with molecular dynamics simulations further supported stable ligand-protein interactions within CDK2, EGFR, and mutant EGFR active sites, with favorable binding energies and conformational stability throughout 100 ns trajectories. Collectively, these findings identify compounds 6e and 8c as promising lead scaffolds for further development of CDK2 or EGFR inhibitors with potent and selective anticancer properties.
Current Advances in Paraptosis Inducer Development and Mechanistic Understanding for Anticancer Applications.
Shen C, Zhang X, Zhao Y … +1 more , Liu S
Drug Dev Res · 2026 Apr · PMID 41773935 · Publisher ↗
Paraptosis is an emerging form of programmed cell death (PCD) that is distinct from conventional cell death modalities such as apoptosis, autophagy, necrosis, and pyroptosis. It is characterized by dilation of the endopl...
Paraptosis is an emerging form of programmed cell death (PCD) that is distinct from conventional cell death modalities such as apoptosis, autophagy, necrosis, and pyroptosis. It is characterized by dilation of the endoplasmic reticulum (ER) and/or mitochondria, accompanied by extensive cytoplasmic vacuolation. This process has garnered significant interest within the realm of cancer treatment in recent years. Therefore, this review provides a comprehensive summary of the potential mechanisms underlying paraptosis and highlights recent progress in the development of paraptosis inducers for cancer therapy. These inducers include natural products, synthetic compounds, and anticancer drugs; moreover, they are frequently employed in combination with other therapeutic strategies. Furthermore, these inducers can trigger paraptosis in cancer cells via multiple pathways, thereby providing a promising alternative therapeutic approach for cancer.
Design, Synthesis, In Vitro and In Vivo Biological Evaluation of Novel Pyrazolo[3,4-d]Pyrimidine-Based Derivatives as Promising Multitarget Candidates for Alzheimer's Disease.
Nemr MTM, Mohamed LW, Sayed HS … +1 more , Mikhail DS
Drug Dev Res · 2026 Apr · PMID 41773918 · Publisher ↗
Multi-target directed ligands (MTDLs) advocate for a novel therapeutic framework for Alzheimer's disease (AD) owing to its complicated multifactorial nature. Therefore, the present study focuses on designing and synthesi...
Multi-target directed ligands (MTDLs) advocate for a novel therapeutic framework for Alzheimer's disease (AD) owing to its complicated multifactorial nature. Therefore, the present study focuses on designing and synthesizing pyrazolo[3,4-d]pyrimidine derivatives, followed by biological evaluation as MTDLs for AD. Most of the obtained derivatives showed potent AChE inhibitory efficacy, significant suppression of Aβ, and pronounced antioxidant activity in vitro. Compound 8b (IC = 0.346 μM) and 9a (IC = 0.168 μM) are the most potent inhibitors of AChE relative to donepezil (IC = 0.213 μM). Furthermore, both 8b (IC = 1.475 μM) and 9a (IC = 1.060 μM) exhibited remarkable Aβ inhibitory activity, surpassing that of donepezil (IC = 7.944 μM). Also, they demonstrated remarkable antioxidant capacity, with an ORAC index of 1.66 and 0.90 Trolox equivalents. The in vivo investigation of the most potent compounds (8b and 9a) revealed a significant improvement in scopolamine-induced cognitive deficits in animals. The molecular docking of compounds 8b and 9a within the human acetylcholinesterase (hAChE) active site showed auspicious binding with both catalytic active site (CAS) and peripheral anionic site (PAS). In addition, molecular dynamics (MD) simulations were employed to investigate the stability of compounds 8b and 9a within the hAChE active site and to support the reliability of the docking analysis. Finally, In silico physicochemical and pharmacokinetics prediction analyses were performed, and the findings were well aligned with their corresponding in vitro results. Overall, the results highlight 8b and 9a as potential multifunctional candidates for AD.
Rational Design and Characterization of 5-Fluorouracil-Loaded Lipid-Polymer Hybrid Nanoparticles for Enhanced Transdermal Delivery in Skin Cancer Therapy.
Dongsar TS, Alqahtani T, Shmrany HA … +3 more , Goh KW, Ahmad FJ, Kesharwani P
Drug Dev Res · 2026 Apr · PMID 41766216 · Publisher ↗
Effective management of skin cancer remains challenging due to limited transdermal drug penetration, systemic toxicity, and therapeutic resistance. In this study, 5-fluorouracil (5-FU)-loaded lipid-polymer hybrid nanopar...
Effective management of skin cancer remains challenging due to limited transdermal drug penetration, systemic toxicity, and therapeutic resistance. In this study, 5-fluorouracil (5-FU)-loaded lipid-polymer hybrid nanoparticles (LPHNPs) were rationally engineered as a next-generation nanocarrier system to overcome these barriers. The hybrid design synergistically combines the structural integrity of polymers with the biocompatibility and permeability-enhancing attributes of lipids. Using a central composite design, formulation parameters were optimized to achieve favorable physicochemical characteristics, yielding nanoparticles with a mean diameter of 256.7 nm, a polydispersity index (PDI) of 0.2711, and a positive zeta potential of +25.47 mV, indicative of excellent colloidal stability. In vitro release and ex vivo permeation studies revealed a sustained drug release profile and significantly improved dermal penetration compared to conventional formulations. Moreover, the Hen's egg test-chorioallantoic membrane (HET-CAM) irritation assay confirmed the biocompatibility and reduced irritation potential of the developed system. Overall, the optimized 5-FU-loaded LPHNPs present a promising platform for localized, controlled transdermal chemotherapy, potentially minimizing systemic exposure and improving therapeutic efficacy in skin cancer management.
Piperidine-Based Hydrazones and Their Pt(II)/Pd(II) Complexes: Synthesis, Structural Characterization, In Vitro Anticancer Evaluation, and In Silico Studies.
Doğan MO, Oruç-Emre EE, Alyamaç İT … +5 more , Taşdemir D, Turgut Solak ZD, Tatar Yilmaz G, Koçyiğit-Kaymakçioğlu B, Tok F
Drug Dev Res · 2026 Apr · PMID 41766180 · Publisher ↗
In this study, 2-(4-methylpiperidin-1-yl)acetohydrazide was condensed with a series of substituted benzaldehydes to afford a library of piperidine-based hydrazones, which were subsequently complexed with K₂PtCl₄ and K₂Pd...
In this study, 2-(4-methylpiperidin-1-yl)acetohydrazide was condensed with a series of substituted benzaldehydes to afford a library of piperidine-based hydrazones, which were subsequently complexed with K₂PtCl₄ and K₂PdCl₄ to yield the corresponding Pt(II) and Pd(II) complexes. The structures of molecules were elucidated by spectral methods and elemental analysis. The in vitro anticancer potential of the compounds was evaluated through cytotoxicity, wound-healing/migration, and RT-qPCR assays in A549 (lung) and HepG2 (hepatocellular) cancer cell lines. In the cytotoxicity studies, compound 3lPd exhibited the highest activity in A549 cells (IC₅₀ = 61.25 ± 0.03 µM), while ligand 3b and complex 3nPt showed the most pronounced effects in HepG2 cells (IC₅₀ = 77.96 ± 0.05 and 77.01 ± 0.02 µM, respectively). The most active compounds were further tested in wound-healing assays, where 3lPd almost completely inhibited A549 cell migration at 24 and 48 h, whereas the reference drug cisplatin induced only partial inhibition. Consistent with these findings, RT-qPCR analysis revealed that in A549 cells, 3lPd markedly suppressed MYC expression and reduced p53 levels to an extent comparable to cisplatin. In HepG2 cells, 3nPt decreased p53 expression, while L3b uniquely upregulated p53 and maintained MYC expression near control levels. In silico studies were performed to investigate their interactions with p53, GAPDH, and c-MYC proteins. Overall, these results suggest that piperidine-bearing hydrazones and their Pt(II)/Pd(II) complexes represent promising scaffolds for the development of novel anticancer agents.
Design and Synthesis of Novel Lonidamine-N-Heterocyclic Derivatives With Potent Anticancer Activity Against Colorectal Cancer Cells.
Bhat RM, An P, Muddapur GV … +5 more , Srinivasa SM, Agrawal M, Imran M, Kalakuntla RK, Keri RS
Drug Dev Res · 2026 Apr · PMID 41766177 · Publisher ↗
Colorectal cancer remains a major health concern and the second leading cause of cancer deaths, underscoring the urgent need for advanced early diagnostic methods to improve survival outcomes. In this study, we designed...
Colorectal cancer remains a major health concern and the second leading cause of cancer deaths, underscoring the urgent need for advanced early diagnostic methods to improve survival outcomes. In this study, we designed and synthesized a new series of hybrid compounds that incorporate Lonidamine and various N-heterocycles, such as pyridine, 4-quinoline, 4,7-chloroquinoline, and acridine. Synthesized compounds were characterized by various spectral techniques, including NMR (H and C), mass spectra, and HPLC. The cytotoxicity studies of the conjugates were conducted using the colorectal cancer cell line (HCT116), and compound (22a) exhibited potent antiproliferative activity, with the lowest IC value of 2.59 ± 0.33 µM, indicating that it is the most potent among the screened compounds. The compound effectively induces apoptosis, as demonstrated by Hoechst/PI double staining in HCT116 cells. The treatment group showed reduced migratory capabilities, highlighting the compound's strong antiproliferative activity and antimigratory propensity against HCT116 cells. Additionally, physicochemical features and ADMET profiles have been investigated to gain a better understanding of their pharmacokinetic and toxicological characteristics. The results demonstrated satisfactory pharmacokinetic behavior and acceptable toxicity profiles, with (22a) emerging as a promising candidate due to its superior bioavailability, enhanced stability, and potent anticancer activity. Molecular docking, dynamics simulations, and DFT studies were used to better understand the SAR and mechanisms of action of potential cancer drugs. This study indicates the promising potential of compound (22a) as a prospective candidate agent for colorectal cancer treatment. Further comprehensive investigations are needed to explore its therapeutic efficacy in greater detail.
Has AI Reshaped Drug Discovery, or Is There Still a Long Way to Go?
Shree Harini K, Ezhilarasan D
Drug Dev Res · 2026 Apr · PMID 41766174 · Publisher ↗
The conventional drug discovery pipeline is labour-intensive, time-consuming, and costly, involving target identification, hit discovery, lead optimization, and extensive preclinical and clinical evaluation. To overcome...
The conventional drug discovery pipeline is labour-intensive, time-consuming, and costly, involving target identification, hit discovery, lead optimization, and extensive preclinical and clinical evaluation. To overcome these limitations, artificial intelligence (AI) has emerged as a transformative tool in drug discovery, gaining widespread adoption in the pharmaceutical industry during the 2010s due to advances in computing power, data availability, and deep learning. AI-based approaches, including molecular property prediction, protein structure modelling, natural language processing, and ADME/Tox prediction, have enhanced efficiency, reduced costs, and improved decision-making across multiple stages of drug development. Several AI-guided molecules have progressed into clinical trials, with encouraging early-phase success rates, highlighting the potential of AI to accelerate innovation. However, despite more than a decade of intensive research, no AI-only originated drug has yet achieved full regulatory approval, reflecting persistent challenges consistent with Eroom's law. Key limitations include poor data quality and accessibility, lack of model interpretability, gaps between computational predictions and chemical feasibility, and the inherent complexity of biological systems that limit translational success. Furthermore, AI-driven hypothesis generation does not replace the need for scientific reasoning and experimental validation. Overall, while AI has significantly accelerated early drug discovery stages, it remains a supportive tool rather than a standalone solution, underscoring the continued need for human expertise and experimental research.
Novel Imidazoquinoline Based TLR7 Agonist Induces Antileishmanial Efficacy-An In Vitro Study.
Thakur S, Kumar K, Kaur S … +4 more , Sanjana, Sihag B, Salunke DB, Kaur S
Drug Dev Res · 2026 Apr · PMID 41693479 · Publisher ↗
Leishmaniasis elimination and control remain challenging due to the lack of successful treatment and possible prevention. A suitable anti-leishmanial medication that is acceptable in terms of price and safety is currentl...
Leishmaniasis elimination and control remain challenging due to the lack of successful treatment and possible prevention. A suitable anti-leishmanial medication that is acceptable in terms of price and safety is currently being researched. In light of this, the current study examined the effectiveness of imidazoquinoline based selective Toll-like receptor (TLR)-7 agonists as anti-leishmanial agents. A library of TLR7 agonists was evaluated for anti-leishmanial efficacy against experimental visceral leishmaniasis (VL). Among all the agonists, 2-butyl-1-(3,4-dimethoxybenzyl)-1H-imidazo[4,5-c]quinolin-4-amine (7) and its niosomal formulation 18 exhibited better activity than Miltefosine. These were then further studied against Leishmania donovani for their ability to arrest the parasites at sub G/G phase of cell cycle. The selected TLR7 agonists depicted their ability to arrest higher percentage of parasites in comparison to the standard antileishmanial drugs. Similar observations were seen in case of reactive oxygen species (ROS) generation where parasites treated with the lead TLR7 agonist produced higher ROS than the untreated parasites. These results suggest that TLR7 agonist 7 and its niosomal formulation 18 could be the promising hits for development of a novel drug treating VL. However additional in-vivo studies could aid in their future advancement.
Structural Exploration of Pyrazine-1,2,3-Triazole Hybrids as Selective Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease.
Ramesh M, Padmaja P, Ugale V … +5 more , Shirkhedkar A, Pawara R, Lokwani D, Manda S, Reddy PN
Drug Dev Res · 2026 Apr · PMID 41685967 · Publisher ↗
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to gradual deterioration of cognitive functions. Cholinesterase enzymes play a critical role in regulating acetylcholine levels in the brain...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to gradual deterioration of cognitive functions. Cholinesterase enzymes play a critical role in regulating acetylcholine levels in the brain, and their dysfunction leads to impaired cholinergic neurotransmission, which is a primary hallmark of AD and contributes significantly to the cognitive decline and dementia. Here, a series of pyrazine-1,2,3-triazole molecular hybrids incorporating a trifluoromethyl (-CF) group were synthesized (8a-o). Synthesized compounds were then evaluated in vitro for cytotoxicity and cholinesterase inhibitory activities. All synthesized compounds were found to be nontoxic toward BV-2 cells in the cytotoxicity screening. The in vitro inhibition assays revealed that these derivatives exhibited greater inhibitory potency against acetylcholinesterase (AChE) than butyrylcholinesterase (BuChE). Among them, compound 8h demonstrated the most potent AChE inhibition compared to BuChE (AChE, IC = 5.43 µM; BuChE, IC = 127.12 µM). The most active compound 8h was further subjected to molecular docking and dynamic simulation (100 ns) to investigate its binding affinity, thermodynamic behavior, and stability within the active site of cholinesterase enzymes. Overall, the findings suggested that the synthesized compounds represent promising drug candidates as selective acetylcholinesterase inhibitors for the treatment of AD.
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