Drug Development Research最新文献

{"title":"Cryptocaryone Exhibits ROS/MAPK-Dependent Antiproliferative and Apoptosis-Inducing Effects on Triple-Negative Breast Cancer Cells and Proof-of-Concept Breast Cancer Mouse Model.","authors":"Ya-Ting Chuang, Wangta Liu, Tsu-Ming Chien, Ammad Ahmad Farooqi, Hsun-Shuo Chang, Jun-Ping Shiau, Hsueh-Wei Chang","doi":"10.1002/ddr.70286","DOIUrl":"10.1002/ddr.70286","url":null,"abstract":"<p><p>Omics' technologies have enabled clinicians to gain previously unprecedented insights into the molecular complexity and clinical heterogeneity of triple-negative breast cancer (TNBC). Increasingly it is being realized that TNBC does not respond well to current targeted therapies. This study aims to explore the antiproliferative effects and cancer regulatory mechanisms which underlie the drug resistance and aggressiveness of TNBC cells. Cryptocaryone (CPC) derived from Cryptocarya concinna demonstrated antiproliferative responses to TNBC cells (HCC1937 and MDA-MB-231), while normal breast cells (H184B5F5/M10) exhibited low cytotoxicity. In an in vivo assessment, CPC effectively reduced tumor growth in the MDA-MB-231 xenografted mouse model without significantly affecting body weight. Mechanistically, CPC triggered apoptosis, as indicated by an increase in sub-G1 and annexin V, as well as activated caspase 3 and 8. CPC also induced substantial oxidative stress by generating reactive oxygen species, mitochondrial superoxide, and membrane depolarization. CPC also induced oxidative DNA damage, as evidenced by the presence of γH2AX and 8-hydroxy-2-deoxyguanosine, in TNBC cells. All these CPC-induced changes were more pronounced in TNBC cells than normal cells. JNK and p38 MAPK inhibitors attenuate CPC-induced antiproliferation in TNBC cells. CPC upregulates phosphorylated JNK and p38 in TNBC cells. N-acetylcysteine pretreatment confirmed that oxidative stress plays a vital role in enhancing the antiproliferation, apoptosis, and DNA damage in TNBC cells. Moreover, the CPC-upregulated apoptosis and caspase 3/8 activations in TNBC cells were inhibited by JNK and p38 inhibitors. The impact of ERK activation on antiproliferation and apoptosis was evident in MDA-MB-231 cells, but not in HCC1937 cells. In conclusion, CPC demonstrated antiproliferative effects on TNBC cells through apoptosis and DNA damage induced by oxidative stress and MAPK activation, while showing drug safety in normal cells and breast cancer mouse model.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 3","pages":"e70286"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13092884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147721876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antitumor Activity of Sodium Selenite, Palbociclib, and Disulfiram Against Osteosarcoma and Rhabdomyosarcoma Cell Lines.","authors":"María Ángeles Chico, Kevin Doello, Raul Ortiz, Mercedes Peña, Consolación Melguizo, Cristina Mesas, Jose Prados","doi":"10.1002/ddr.70304","DOIUrl":"10.1002/ddr.70304","url":null,"abstract":"<p><p>Osteosarcoma and rhabdomyosarcoma are the most common pediatric sarcomas, yet prognosis remains poor due to high relapse rates. This study investigates the repurposing of palbociclib (PB) and disulfiram (DS), alongside sodium selenite (SS), as potential therapeutic strategies. Using cell lines, we assessed antiproliferative effects via Sulforhodamine B, colony formation, and wound healing assays. Mechanisms of action were explored through protein expression of PARP-1 (apoptosis) and LC3β (autophagy), qPCR for stem cell markers, and ROS quantification. Finally, antitumor and anti-angiogenic efficacy was validated using the in ovo chicken chorioallantoic membrane (CAM) assay. Results demonstrated that all three compounds inhibited proliferation, migration, and spheroid growth while inducing apoptosis and autophagy. Notably, SS and PB elevated ROS levels, triggering parthanatos-mediated cell death via AIF nuclear translocation. SS also exhibited significant anti-angiogenic activity. Xenograft CAM models confirmed the in vivo efficacy of SS, PB, and DS against RD and MG63 cells. These findings suggest that SS, PB, and DS are promising candidates for pediatric sarcoma treatment, particularly as maintenance therapies to prevent relapse following conventional radical treatment.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 3","pages":"e70304"},"PeriodicalIF":4.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Alpha-Synuclein Aggregation With Chemical Chaperone IP-045: An Approach to Parkinson's Disease Therapy","authors":"Navpreet Kaur,&nbsp;Rimaljot Singh,&nbsp;Neelima Dhingra,&nbsp;Tanzeer Kaur","doi":"10.1002/ddr.70288","DOIUrl":"https://doi.org/10.1002/ddr.70288","url":null,"abstract":"<div>\u0000 \u0000 <p>Protein misfolding and aggregation of alpha-synuclein (α-syn) are central to Parkinson's disease (PD). Current therapies provide only symptomatic relief without addressing α-syn aggregation. Chemical chaperones such as 4-phenylbutyrate (4-PBA) and tauroursodeoxycholic acid (TUDCA) show promise but are limited by toxicity and high dosage requirements. This study aimed to develop a safer, more effective multi-target compound to counter α-syn aggregation and related cellular stress. To design, synthesize, and evaluate a novel multi-target chemical chaperone, IP-045, for inhibiting α-syn aggregation and ameliorating PD pathology. A structure-based virtual screen of &gt;11,000 compounds against the α-syn fibril structure (PDB ID: 6UFR) identified four candidates with favorable pharmacokinetics. In vitro aggregation assays and SHSY5Y cell models assessed anti-aggregation activity, cytotoxicity, and modulation of rotenone-induced α-syn expression, oxidative stress, and ER stress. The lead compound, IP-045 (2-Fluorophenyl 3-(1H-indol-3-yl)propanoate), was synthesized and tested in a rotenone-induced PD rat model through behavioral, histological, and molecular analyses. IP-045 strongly inhibited α-syn aggregation in vitro with minimal cytotoxicity. In cell-based assays, it reduced reactive oxygen species, ER stress markers, and α-syn expression. In vivo, IP-045 improved motor coordination, memory, and cognitive performance. Immunohistochemistry showed reduced Ser129-phosphorylated α-syn and restored tyrosine hydroxylase. IP-045 also suppressed apoptotic and pro-inflammatory markers in the substantia nigra, confirming multi-target neuroprotective activity. IP-045 demonstrated favorable anti-aggregation and neuroprotective effects across in vitro and in vivo models, indicating its potential as a promising lead compound with chaperone-like activity for targeting pathological processes associated with PD. Further pharmacokinetic, toxicity, and mechanistic studies are warranted to support its future therapeutic development.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147715258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preparation of Aaptamine-Loaded Fusogenic Liposomes and Evaluation of Its Enhanced Antibacterial Activity Against MRSA","authors":"Tianjiao Geng,&nbsp;Guoqiang Hou,&nbsp;Yingqiu Liu,&nbsp;Haitao Xue,&nbsp;Xiaoyan Zou,&nbsp;Zhichun Gu,&nbsp;Houwen Lin","doi":"10.1002/ddr.70279","DOIUrl":"10.1002/ddr.70279","url":null,"abstract":"<p>The global threat of methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) necessitates the development of novel therapeutic strategies. Our previous work identified A7, a marine-derived aaptamine alkaloid, as a potential anti-MRSA agent. However, its clinical translation is limited by poor membrane permeability and unclear antibacterial mechanism. Targeting antimicrobial agents by liposomes may be a valid strategy in the treatment of infections refractory to conventional routes of antimicrobial treatment. Therefore, this study aimed to develop A7-loaded fusogenic liposomes (A7@FLP) as a targeted drug delivery system. Fusogenic liposomes loaded with A7 were produced and characterized, with the objectives of examining their improved cellular penetration, antibacterial activity, and inhibitory mechanism against MRSA. The results showed that FLP was successfully developed with a size 128.9 ± 2.2 nm. A7@FLP exhibited sustained release and significantly enhanced anti-MRSA activity in a dose-dependent manner. It achieved a minimum inhibitory concentration (MIC) of 1 μg/mL, which showed 2-fold improvement over free A7 (2 μg/mL). Further mechanistic studies revealed that A7@FLP damaged bacterial wall and membrane integrity, thereby disrupting cellular physiological functions and triggering oxidative stress-mediated cell death. The antibacterial effect was found to be multitargeted, involving oxidative stress, lipid peroxidation, membrane damage, and energy metabolism dysfunction. In conclusion, these findings affirm that A7-loaded fusogenic liposomes represent a highly promising therapeutic candidate for combating MRSA infections.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147644359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the NLRP3 Inflammasome: Novel Inhibitors for Cardiovascular Diseases Management — A Narrative Review","authors":"Yomna S. Momen","doi":"10.1002/ddr.70283","DOIUrl":"10.1002/ddr.70283","url":null,"abstract":"<div>\u0000 \u0000 <p>The innate immune system is the first line of defense against pathogens and intracellular danger signals, providing a rapid nonspecific response to eliminate the infection and maintain tissue homeostasis. NLRP3 (NLR family pyrin domain containing 3) inflammasome, as a critical component of the innate immune system, plays a pivotal role in the inflammatory response. Many research studies have highlighted the implication of NLRP3 in the pathogenesis of various cardiovascular diseases including atherosclerosis, myocardial infarction, hypertension and heart failure. Activation of NLRP3 elicits a robust inflammatory response represented in proteolytic cleavage and release of pro-inflammatory cytokines such as IL-1β and IL-18, which contribute to the progression of vascular inflammation and myocardial damage. This narrative review aims to comprehensively summarize the current evidence of NLRP3 inflammasome activation in cardiovascular diseases, elucidate the underlying molecular mechanisms, and critically evaluate emerging NLRP3 inhibitors. Particular emphasis is placed on novel synthetic small-molecule inhibitors and bioactive phytoestrogens targeting NLRP3 as potential therapeutic strategies. Collectively, targeting NLRP3 represents a new frontier in cardiovascular disease management. However, further research is needed to optimize these compounds in preclinical models and to explore their efficacy and safety in human studies, paving the way for innovative treatments that could transform the management of cardiovascular diseases.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 2","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147644353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and Synthesis of Bis-3,4-Dimethoxybenzene-Fibrate Derivatives as Potential Lipid-Lowering and Hepatoprotective Agents Based on the Principles of Structural Simplification and Bioisosterism.","authors":"Ling Ding, Yuyu An, Huizi Shangguan, Xin Wang, Jiping Liu, Huanxian Shi, Yongheng Shi, Xinya Xu, Yundong Xie","doi":"10.1002/ddr.70271","DOIUrl":"https://doi.org/10.1002/ddr.70271","url":null,"abstract":"<p><p>A series of bis-3, 4-dimethoxy-fibrate derivatives was designed using structural simplification and bioisosteric principles. The hypolipidemic effects of these compounds were initially evaluated in a Triton WR 1339-induced hyperlipidemic mouse model. The results indicated that compound T4 significantly reduced in levels of triglycerides (TG) and total cholesterol (TC). The dosage-dependent results show that reductions in TG and TC are greater as the T4 dosage increases. In the high-fat diet-induced hyperlipidemia model, T4 was found to significantly lower TG, TC, and LDL-C levels. Moreover, T4 exhibited hepatoprotective effects by substantially reducing levels of aspartate transaminase (AST) and alanine transaminase (ALT) in the liver. Histopathological examination indicated that T4 could inhibit hepatic lipid deposition and alleviate liver injury. Mechanistic investigations indicate that T4 upregulates hepatic peroxisome proliferator-activated receptor-alpha (PPAR-α) protein expression, contributing to its lipid-lowering effects. Molecular docking research has indicated a strong affinity between T4 and the active site of PPAR-α. Furthermore, T4 has demonstrated antioxidant and anti-inflammatory properties. These results suggest T4 could function as both an effective lipid-lowering compound and a potential hepatoprotective agent.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 2","pages":"e70271"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147580841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Antioxidant Quinazoline Sulfonamide Derivatives Acting Through NQO1 Induction and Their Radiation-Based Biodistribution Studies.","authors":"Mostafa M Ghorab, Aiten M Soliman, Maureen Higgins, Albena T Dinkova-Kostova, Mohamed A Amin, Mohamed Korany, Mohammed A Khedr, Tamer M Sakr","doi":"10.1002/ddr.70274","DOIUrl":"https://doi.org/10.1002/ddr.70274","url":null,"abstract":"<p><p>A series of quinazoline derivatives 5-19 bearing a benzenesulfonamide moiety and different acetamide side chains, including aromatic and heterocyclic groups, were designed, synthesized and confirmed structurally by microanalytical and spectral data. The obtained compounds were evaluated in vitro for their ability to activate nuclear factor erythroid 2-related factor 2 (Nrf2) through induction of NAD(P)H: quinone oxidoreductase 1 (NQO1) in Hepa1c1c7 murine hepatoma cells. Compounds 15 and 18 exhibited the highest potency with CD values of 2.5 and 5 µM, respectively. The most potent derivatives (15 and 18) were further evaluated for their antioxidant potential using DPPH, with compound 18 demonstrating the highest radical scavenging activity. A radiation-based biodistribution study was conducted using 18 and displayed marked selectivity toward tumor cells over normal cells. Molecular docking studies and molecular dynamics simulations demonstrated that 18 exhibits a strong binding affinity and forms key stabilizing interactions within the Nrf2-binding domain of Kelch-like ECH-associated protein 1 (Keap1). These results demonstrate that quinazoline sulfonamide derivatives are promising oxidative stress modulators with tumor targeting ability.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 2","pages":"e70274"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147590714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A LAT1-Compatible, Leadlike Tyrosine-Naphthoquinone Conjugate With Anticancer Activity.","authors":"Austin Seymour, Christian Peterson, Raymond Osafo, Abdullahi A Ashimi, Dylan Williams, Laura Echezabal, Chelsea Carrier, Alysa Clarke, Clifford W Padgett, Mark Vincent C Dela Cerna, Zheni Utic, Divine Wanduku, Nathaniel Shank, Karelle S Aiken, Jannet Kocerha","doi":"10.1002/ddr.70269","DOIUrl":"10.1002/ddr.70269","url":null,"abstract":"<p><p>A L-type amino acid transporter 1 (LAT1)-compatible, anticancer-active tyrosine-naphthoquinone (NQ) conjugate was successfully developed. The conjugate was designed to exploit LAT1 overexpression in cancers with the goal of achieving selective cytotoxicity for cancerous over noncancerous cells. The tyrosine-NQ molecule was subjected to cell viability, imaging, docking and in silico pharmacological studies along with structure-activity relationship (SAR) assessment. Cell viability investigations included IC₅₀ and substrate-competition studies. Cells of cancerous (PC3) and noncancerous (HEK293) origin with high and minimal expressions of LAT1, respectively, were employed for biochemical investigations. The tyrosine-NQ assembly showed significant cytotoxic selectivity toward PC3 over HEK293, with activity comparable to that of the parent molecule NQ and doxorubicin (DOX), an approved drug. Docking studies demonstrated that the conjugate is LAT1-compatible as it interacts with key residues along the protein's transport pathway. Cell viability competition studies verify a LAT1-facilitated uptake. SAR studies revealed that the conjugate's anticancer activity is due to its aryloxy-naphthoquinone motif. In silico pharmacological investigations determined that the conjugate is leadlike and therefore, well-suited for structural modifications for further drug development. Finally, imaging investigations showed that, with PC3, the conjugate caused drug-induced stress-responses in nuclear morphology. Overall, findings demonstrate that the tyrosine-NQ conjugate is a promising lead for the design of LAT1-targeting, NQ-based chemotherapeutics.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 2","pages":"e70269"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13044391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147590770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heteromerization, Biased Agonism, and Allosteric Modulation of G Protein-Coupled Receptors in Addiction: Mechanistic Insights and Therapeutic Implications.","authors":"Khaled A Alhosaini, Mohammed M Alanazi, Ibrahim N Alsulaihim, Asma S Alonazi, Fawaz F Alasmari, Mohammad R Khan","doi":"10.1002/ddr.70273","DOIUrl":"https://doi.org/10.1002/ddr.70273","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 2","pages":"e70273"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147572865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, Synthesis, In Silico Profiling, and In Vitro Anticancer Assessment of Azine-Linked Thiazolo[3,2-a]benzimidazoles as CDK2-Directed Therapeutic Candidates.","authors":"Mohamed S M Ahmed, Sayed M Riyadh, Mohammad Alhilal, Magdi E A Zaki, Suzan Alhilal, Mohamed El-Naggar, Wesam Hussein, Ahmed A Elhenawy, Sobhi M Gomha","doi":"10.1002/ddr.70272","DOIUrl":"https://doi.org/10.1002/ddr.70272","url":null,"abstract":"<p><p>A series of unsymmetrical azine-linked thiazolo[3,2-a]benzimidazole derivatives (4a-r) was synthesized and structurally characterized. Density functional theory (DFT) calculations, including frontier molecular orbital (FMO) analysis and global reactivity descriptors, supported the preferential formation of the E-isomeric forms. In silico target prediction prioritized cyclin-dependent kinase 2 (CDK2), and molecular docking of representative active members (4b, 4 d, 4p, and 4r) revealed key contacts around Arg83/Pro84 and favorable binding energies ( - 3.91 to -6.20 kcal/mol). In vitro antiproliferative activity against human colon carcinoma (HCT-116) and human hepatocellular carcinoma (HepG2) cell lines identified 4r as the most potent compound (half-maximal inhibitory concentration, IC₅₀ = 5.26 ± 0.37 and 5.03 ± 0.42 µM, respectively), surpassing doxorubicin (IC₅₀ = 7.05 ± 0.49 and 6.42 ± 0.31 µM). Absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction indicated high gastrointestinal (GI) absorption, no blood-brain barrier (BBB) permeation, no P-glycoprotein (P-gp) substrate liability, a bioavailability score of 0.55, and zero pan-assay interference compounds (PAINS) alerts. Overall, the integrated synthetic, computational, and biological results highlight azine-linked thiazolo[3,2-a]benzimidazoles, particularly 4r, as promising CDK2-directed anticancer leads.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"87 2","pages":"e70272"},"PeriodicalIF":4.2,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147590706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}