Archiv der Pharmazie最新文献

{"title":"K+ Channels in Membrane Potential Dynamics and Migration of Neutrophil Granulocytes","authors":"Tahir Ulu,&nbsp;Henrik Siemer,&nbsp;Alexa Heuer,&nbsp;Sandra Schimmelpfennig,&nbsp;Peter Dieterich,&nbsp;Jesús Borrego,&nbsp;György Panyi,&nbsp;Albrecht Schwab","doi":"10.1002/ardp.70365","DOIUrl":"10.1002/ardp.70365","url":null,"abstract":"<p>Neutrophil granulocytes exhibit dynamic changes in membrane potential upon stimulation with the complement component C5a. It is not well-defined which ion channels are responsible for membrane potential dynamics in neutrophils, although ion channel signaling has been linked to neutrophil behavior. Here, we investigated the contribution of K⁺ channels that are important players in different immune cells: K_Ca3.1, K_ir2.1, and K_V1.3. We studied their roles in membrane potential regulation, chemotaxis, and LTB4 secretion using live-cell imaging, analytical methods, and mathematical modeling. We identify membrane potential dynamics as an important regulatory axis in neutrophil migration. K_ir2.1 is a key regulator of resting membrane potential. K_ir2.1 blockade depolarizes the membrane potential of neutrophils by ~30 mV to −41.9 mV, and it delays and attenuates the C5a-induced depolarization. In contrast, K_Ca3.1 and K_V1.3 inhibition neither modifies the resting membrane potential nor the C5a-induced depolarization. Nonetheless, the inhibition of all three K⁺ channels impairs chemotaxis toward C5a, in part by a reduced LTB₄ secretion and/or possibly by non-conductive properties related to the interactome of the three K⁺ channels. Together, these findings demonstrate that K_Ca3.1, K_V1.3 and K_ir2.1 channels play distinct but critical roles in neutrophil function and inflammatory signalling.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 10","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70365","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149190131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-Canonical Modulation of Vitamin D Receptor Signaling by Paclitaxel in Triple-Negative Breast Cancer","authors":"Agustina Ibarra,&nbsp;María Julia Ferronato,&nbsp;Valentina Clemente,&nbsp;Josefina Guevara,&nbsp;Alfredo Quevedo,&nbsp;Karen Schweitzer,&nbsp;Exequiel Gonzalo Alonso,&nbsp;Ignacio Bergé,&nbsp;Anabel Barrientos,&nbsp;Georgina Pamela Coló,&nbsp;Uxia Gómez-Bouzó,&nbsp;Generosa Gómez,&nbsp;Yagamare Fall,&nbsp;Eliana Noelia Alonso,&nbsp;Ezequiel Lacunza,&nbsp;María Eugenia Fermento,&nbsp;Alejandro Carlos Curino,&nbsp;María Marta Facchinetti","doi":"10.1002/ardp.70360","DOIUrl":"10.1002/ardp.70360","url":null,"abstract":"<div>\u0000 \u0000 <p>Triple-negative breast cancer (TNBC) is characterized by a highly aggressive phenotype and limited therapeutic options. This study investigated whether the vitamin D receptor (VDR) modulates aggressiveness and chemotherapeutic response in TNBC and explored its interaction with paclitaxel (PTX) in the presence of a non-hypercalcemic vitamin D analogue (UVB1). Functional cellular assays, orthotopic murine models, and computational approaches were integrated using murine 4T1 and human MDA-MB-468 TNBC cells with differential VDR expression, including PTX-resistant models. The results show that VDR overexpression reduced invasive capacities in vitro and pulmonary metastatic dissemination in vivo, and sensitized cells to PTX alone or combined with UVB1. 4T1-PTX-resistant cells exhibited elevated VDR levels and less aggressive features compared with wild-type cells. Computational analyses revealed stable PTX binding to an allosteric site near the activation function-2 domain of VDR, further stabilized by UVB1. Functional assays demonstrated that the combination of PTX and UVB1 enhanced the transcriptional activity of VDR compared with UVB1 treatment alone. These findings identify VDR signaling as a modulator of tumor aggressiveness and PTX response in TNBC and support a model in which PTX contributes to nuclear receptor regulation, thus highlighting the relevance of non-canonical drug–receptor interactions in shaping cellular responses to chemotherapy.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 10","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149178138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of Some New Xanthine Derivatives and Evaluation of DPP IV Inhibitory Activities","authors":"Erol Akgün,&nbsp;Leyla Yurttaş,&nbsp;Sevde Nur Biltekin Kaleli,&nbsp;Derya Osmaniye,&nbsp;Barkın Berk,&nbsp;Şeref Demirayak","doi":"10.1002/ardp.70362","DOIUrl":"10.1002/ardp.70362","url":null,"abstract":"<div>\u0000 \u0000 <p>Dipeptidyl peptidase IV (DPP IV) inhibition prolongs incretin activity and represents an established therapeutic strategy for the management of type 2 diabetes mellitus. To investigate the underexplored combination of benzyl groups at the N7 position and a piperazine-linked arylthiazole moiety at the C8 position of the xanthine scaffold, 15 novel compounds (<b>6a–6o</b>) were synthesised. The synthetic route involved bromination at the C8 position of theophylline, introduction of benzyl groups at the N7 position, replacement of the bromine atom at the C8 position with piperazine, and subsequent cyclocondensation with phenacyl thiocyanate derivatives. All final compounds were characterised by ¹H and ¹³C NMR spectroscopy, high-resolution accurate-mass mass spectrometry, and analytical HPLC. All derivatives inhibited DPP IV in the low-nanomolar range, with compounds <b>6c</b> and <b>6b</b> showing the highest activities, with IC₅₀ values of 3.95 ± 0.53 and 4.04 ± 0.65 nM, respectively. NIH3T3 cytotoxicity IC₅₀ values ranged from 28.52 to 397.63 µM, indicating substantial preliminary concentration margins relative to DPP IV inhibition. Molecular docking, 100 ns molecular dynamics simulations, interaction-fingerprint analyses and trajectory-based MM/PBSA calculations supported persistent interactions with key DPP IV active-site residues. These results identify the synthesised derivatives, particularly <b>6b</b> and <b>6c</b>, as promising lead structures for further optimisation.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 10","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149178193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carbocisteine Confers Renoprotection in Streptozotocin-Induced Diabetic Nephropathy Through Sirt-1/Nrf-2-Dependent Inhibition of NLRP3 Inflammasome Activation","authors":"Omnia A. Nour,&nbsp;Mahmoud M. Samaha","doi":"10.1002/ardp.70356","DOIUrl":"10.1002/ardp.70356","url":null,"abstract":"<div>\u0000 \u0000 <p>Diabetic nephropathy (DN) is a leading cause of end-stage renal disease, largely driven by oxidative stress and inflammation. This study evaluated the protective role of carbocisteine, a mucolytic with antioxidant and anti-inflammatory properties, against streptozotocin (STZ)-induced DN in rats. Male Sprague–Dawley rats were divided into four groups: normal, diabetic, carbocisteine (250 mg/kg), and carbocisteine (500 mg/kg). After 8 weeks, diabetic rats showed significant hyperglycemia, weight loss, renal dysfunction (elevated serum creatinine, BUN, and urinary protein), oxidative stress (increased MDA, decreased GSH), and upregulation of inflammatory mediators; IL-1β, IL-6, and TNF-α, along with downregulation of Sirt-1 and Nrf-2 expression and upregulation of NLRP3 and caspase-1. Moreover, diabetic rats exhibited a pro-apoptotic shift, characterized by increased Bax and decreased Bcl-2 expression. Histopathology revealed mesangial expansion, tubular degeneration, and interstitial fibrosis. Carbocisteine treatment, particularly at the high dose, significantly improved renal function, attenuated oxidative and inflammatory responses, restored Sirt-1 and Nrf-2 levels, suppressed NLRP3/caspase-1 activation, and reversed the Bax/Bcl-2 imbalance, thereby ameliorating histopathological damage. These findings suggest that carbocisteine exerts nephroprotective effects in diabetic rats through modulation of the Sirt-1/Nrf-2/NLRP3/caspase-1 signaling axis and regulation of the Bax/Bcl-2 apoptotic pathway, highlighting its potential as a promising adjunct therapy for DN.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 10","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic Stress Shifts the Function of KCa3.1 Channels in Pancreatic Beta Cells From a Regulator of Membrane Potential to a Proapoptotic Factor","authors":"Jurek Hense,&nbsp;Lena Beuke,&nbsp;Christina Kick,&nbsp;Bernhard Wünsch,&nbsp;Martina Düfer","doi":"10.1002/ardp.70344","DOIUrl":"https://doi.org/10.1002/ardp.70344","url":null,"abstract":"<p>Metabolic stress increases the whole-cell current through K_Ca3.1 channels in mouse pancreatic islet cells. The study aimed to analyze the network between ion channels mediating Ca²⁺ influx for K_Ca3.1 channel activation and stress-related changes. The physiologically important K_slow current of beta cells was not altered in total but the contribution of K_Ca3.1 current was reduced after culture in the presence of high glucose and palmitate concentrations. Electrical activity was increased by blocking K_Ca3.1 channels with senicapoc in islets cultured under standard conditions but not after metabolic stress. Of note, the functional coupling of K_Ca3.1 to <span>l</span>-type Ca²⁺ channels was severely reduced by metabolic stress, whereas the coupling to Ca²⁺-influx via NMDA receptors increased. Mitochondrial membrane potential of beta cells was not affected by senicapoc but by a mitochondria-targeted derivative. Inhibition of K_Ca3.1 channels by senicapoc or maurotoxin partly protected from apoptosis. In conclusion, the data indicate a shift in the interplay of Ca²⁺-conducting ion channels and the plasma membrane-localized K_Ca3.1 channel. K_Ca3.1 channels changed from an important regulator of membrane potential oscillations to a dysfunctional and proapoptotic factor. This switch might be involved in the decline of islet cell mass and function during progression of type 2 diabetes mellitus.</p>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 10","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.70344","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149146442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, Synthesis, and Anticancer Evaluation of Novel Chalcone Derivatives Bearing Piperazine and Morpholine Moieties","authors":"Nedime Çalışkan,&nbsp;Fatih Yılmaz,&nbsp;Ozan Emre Eyüpoğlu,&nbsp;Mustafa Emirik,&nbsp;Emre Menteşe","doi":"10.1002/ardp.70357","DOIUrl":"https://doi.org/10.1002/ardp.70357","url":null,"abstract":"<div>\u0000 \u0000 <p>Cancer remains one of the leading causes of mortality worldwide, highlighting the need for novel anticancer agents with improved efficacy and selectivity. In this study, a series of chalcone derivatives bearing phenylpiperazine, 2-fluorophenylpiperazine, and morpholine moieties (<b>1a–g</b>, <b>2a–g</b>, and <b>3a–g</b>) were designed, synthesized, and evaluated for their anticancer potential. The target compounds were synthesized via Claisen–Schmidt condensation under basic conditions and characterized by ¹H NMR, ¹³C NMR, and elemental analysis. Their cytotoxic activities were assessed against PC-3, PANC-1, A549, and MCF-7 cancer cell lines using the MTT assay, with HEK-293 cells serving as a non-cancerous control. Most compounds exhibited notable antiproliferative activity and favorable selectivity compared with doxorubicin, cisplatin, and gemcitabine. Among the tested cell lines, A549 cells were the most sensitive. Compounds <b>2d</b>, <b>2b</b>, <b>2c</b>, <b>2e</b>, <b>2g</b>, and <b>2a</b> showed particularly potent activity against A549 cells, with IC₅₀ values of 5.35 ± 0.08, 5.71 ± 0.09, 5.95 ± 0.09, 5.83 ± 0.09, 5.94 ± 0.09, and 5.96 ± 0.09 µM, respectively. Notably, <b>2c</b> exhibited the highest selectivity toward A549 cells (SI = 3.26). SAR analysis indicated that the 2-fluorophenylpiperazine moiety enhanced anticancer activity, while halogen substitution generally improved potency and selectivity. Induced Fit Docking and Glide XP simulations supported these findings, suggesting that <b>2d</b> and <b>2c</b> achieve their activity through key hinge-region anchoring and isoform-specific interactions with PI3K-α and PI3K-γ. Overall, these findings identify fluorinated chalcone derivatives, particularly <b>2d</b>, as promising leads for further anticancer drug development.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 10","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149146294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Acridone-Based EGFR Inhibitors: Design, Synthesis, and Integrated In Silico–In Vitro Evaluation","authors":"Nilam Bhusare,&nbsp;Maushmi S. Kumar","doi":"10.1002/ardp.70354","DOIUrl":"https://doi.org/10.1002/ardp.70354","url":null,"abstract":"<div>\u0000 \u0000 <p>The epidermal growth factor receptor (EGFR) family is a key biomarker and therapeutic target for cancer therapy. Although acridone scaffolds have previously inhibited other tyrosine kinases, their specific targeting of EGFR has not been reported. This study provides novel acridone-N-aceto/benzohydrazide derivatives with anti-EGFR activity. Cytotoxicity screening revealed <b>AE4</b>, <b>AE11</b>, and <b>AF11</b> as highly effective against the A-431 cell line, with IC₅₀ values 3.22 µM, 2.43 µM, and 4.06 µM, respectively, keeping Erb as a standard with an IC₅₀ of 1.62 µM. In vitro EGFR kinase assays confirmed their inhibition, with IC₅₀ values of 3.95 µM (<b>AE4</b>), 3.49 µM (<b>AE11</b>), and 4.45 µM (<b>AF11</b>), selectively reduced p-EGFR Tyr¹⁰⁶⁸ and ERK1/2 levels in a dose-dependent manner, while inducing G₀/G₁ cell-cycle arrest and apoptosis. SAR indicates isopropyl substitutions on the phenyl ring and 2-methoxy on the acridone ring are important for anti-proliferative activity. Notably, <b>AE4</b> exhibited a high DNA-binding affinity (K_b = 7.41 × 10³M⁻¹), suggesting that its efficacy might be due to DNA intercalation. In contrast, <b>AE11</b> and <b>AF11</b> demonstrated significant cytotoxicity, implying the involvement of the RAS/ERK downregulating pathway. Molecular docking indicated favorable EGFR active site interactions. In silico studies predicted oral bioavailability and low toxicity, supported by kinetic solubility and plasma stability assays, highlighting their potential as selective p-EGFR Tyr¹⁰⁶⁸ inhibitors for further development.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 10","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149146443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated In Silico and In Vitro Investigation of Chromene Derivatives as Potential Antidiabetic Agents in 3T3-L1 Cells","authors":"Ankit Verma,&nbsp;Animesh Majumdar,&nbsp;Ozair Alam,&nbsp;Manju Sharma","doi":"10.1002/ardp.70361","DOIUrl":"https://doi.org/10.1002/ardp.70361","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 <p>Type 2 diabetes mellitus is characterized by a progressive decline in insulin sensitivity and represents an important therapeutic target for improving glucose homeostasis. Chromen-derived compounds have attracted interest as potential antidiabetic agents because of their diverse pharmacological activities. Drug-likeness and pharmacokinetic properties were evaluated using ADME profiling. In silico docking and simulation analyses were performed to characterize ligand–protein interactions and evaluate the stability complex with carbohydrate-hydrolyzing enzymes. In vitro studies included MTT assay for cell viability/tolerability, α-glucosidase and α-amylase inhibition assays and 2-deoxyglucose (2-DG) uptake in 3T3-L1 cells. Conventional RT-PCR was further performed to assess PI3K and GLUT-4 mRNA expression. The 2-DG assay provided a functional measure of cellular glucose uptake under the experimental conditions and was not designed to directly establish insulin sensitization. Both compounds showed favorable predicted drug-like and pharmacokinetic properties. Docking and MD analyses predicted favorable ligand–enzyme interactions and complex stability. Experimentally, 7-methoxy-3-Phenyl-4H-Chromen-4-one showed stronger α-glucosidase inhibition, higher 2-DG uptake and marked upregulation of PI3K and GLUT-4 expression, whereas 7,8-Dihydroxy-3-(4-hydroxyphenyl)-4H-chromen downregulated PI3K, modestly increased GLUT-4 and showed lower 2-DG uptake. The findings indicate potential antidiabetic activity through complementary effects on carbohydrate digestion and cellular glucose handling. 7-methoxy-3-Phenyl-4H-Chromen-4-one showed the most consistent response among the chromen derivatives evaluated and emerged as a candidate for further investigation. The present findings do not establish direct activation of insulin-signaling pathway or reversal of insulin resistance. Comprehensive mechanistic investigations, together with in vivo validation, are needed to further substantiate the therapeutic potential of the compound.</p>\u0000 </section>\u0000 </div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 10","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149146286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and Evaluation of New Nitrofuranylamides With Collection of Mycobacterium tuberculosis Clinical Strains From Multidrug-Resistant Tuberculosis High-Burden Country","authors":"Georgi M. Dobrikov,&nbsp;Marine Dogonadze,&nbsp;Anna Vyazovaya,&nbsp;Violeta Valcheva,&nbsp;Viacheslav Zhuravlev,&nbsp;Igor Mokrousov","doi":"10.1002/ardp.70355","DOIUrl":"10.1002/ardp.70355","url":null,"abstract":"<div>\u0000 \u0000 <p>Emergence of drug-resistant <i>Mycobacterium tuberculosis</i> necessitates the development of new drugs. Here, we studied the activity of new piperazine nitrofuranylamides against a collection of clinical strains from an multidrug-resistant tuberculosis (MDR-TB) high-burden country. A series of nitrofuranylamides <b>9–15</b> was synthesized and evaluated using a collection of diverse clinical strains representing globally spread genotypes (Beijing, LAM, and Haarlem; susceptible, MDR, and pre-extensively drug resistant). Minimal inhibitory concentrations (MIC) were determined using a resazurin assay. Whole-genome sequencing was performed on an Illumina HiSeq platform. Although clinical isolates differed in their MICs, some tested compounds—namely <b>11</b> and <b>12</b>—showed higher MICs regardless of the clinical strain. In contrast, compounds <b>13–15</b> exhibited promising activity (MIC &lt; 0.1 µg/mL) against the majority of strains. Moreover, <b>13</b> and <b>14</b> were previously shown to have low toxicity in JCL:ICR mice and low cytotoxicity against human cell lines. A closer look at structural variation indicated that the presence of a pyridine- or quinoline-type aryl substituent leads to a broader spectrum of activity. The additional nitro group in <b>14</b> appears to contribute significantly to its activity. A nonsynonymous mutation in the efflux pump gene <i>Rv3728</i> (372 A &gt; V, GCC → GTC) in one of the Haarlem genotype strains may speculatively correlate with its high-level intrinsic resistance to nitrofurans. Further biological research is warranted to investigate the mechanism of action of the most promising compounds.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 10","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Indole Hybrids: Emerging EGFR-Targeted Agents With Multifaceted Anticancer Properties (2021–Present)","authors":"Bin Zhang,&nbsp;Yun Wang,&nbsp;Shifang Wen,&nbsp;Zhengqiao Liu,&nbsp;Bing Zhao,&nbsp;Lumei Dai","doi":"10.1002/ardp.70334","DOIUrl":"10.1002/ardp.70334","url":null,"abstract":"<div>\u0000 \u0000 <p>The epidermal growth factor receptor (EGFR) is a validated therapeutic target for EGFR-mutant non-small cell lung cancer (NSCLC) and colorectal cancer, yet secondary T790M/C797S mutations and mesenchymal–epithelial transition factor (MET) amplification confer profound resistance to first-, second-, and third-generation EGFR tyrosine kinase inhibitors (TKIs). Indole hybrids integrate indole cores (including azaindoles and fused indoles) with diverse pharmacophores to achieve multi-site binding within the EGFR ATP pocket, conferring higher selectivity toward mutant EGFR than mono-indole scaffolds. This review systematically summarizes indole-based EGFR hybrids reported from 2021 to date into three categories: Phase I/II clinical candidates (<b>1</b>, <b>10</b>), C797S-resistant preclinical leads (<b>11a</b>, <b>14a</b>, <b>34</b>, <b>48a</b>, and <b>50a</b>), and structurally diversified analogs with favorable blood–brain barrier (BBB) permeability and low systemic toxicity. Optimized indole hybrids exhibit prominent advantages over commercial TKIs, including enhanced binding affinity toward mutant EGFR, optimized pharmacokinetic profiles, minimized off-target effects, and the capacity to suppress compensatory oncogenic signals. We comprehensively dissect their binding modes, structure–activity relationships (SARs), in vitro/in vivo anticancer activities, and pharmacological features, and summarize critical substituent optimization rules for overcoming resistance. This work establishes a systematic structural basis for rational development of next-generation indole EGFR inhibitors against refractory EGFR-driven malignancies.</p></div>","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"359 10","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}