European Journal of Medicinal Chemistry Reports最新文献

{"title":"NOC4L serves as a novel prognostic marker and therapeutic target for lung adenocarcinoma","authors":"Mingming Wang ,&nbsp;Yang Lv ,&nbsp;Zhenyu Wang ,&nbsp;Richard Mprah ,&nbsp;Yinchuan Ding ,&nbsp;Cui Li ,&nbsp;Min Xue","doi":"10.1016/j.ejmcr.2025.100274","DOIUrl":"10.1016/j.ejmcr.2025.100274","url":null,"abstract":"<div><h3>Background</h3><div>Nucleolus complex-associated 4 homologue (NOC4L), a ribosome biogenesis factor essential for small subunit processome assembly, has demonstrated oncogenic potential across multiple malignancies. Nevertheless, the mechanistic contributions of NOC4L to lung adenocarcinoma (LUAD) pathogenesis remain poorly characterized. This study systematically investigates the expression, clinical relevance, and molecular functions of NOC4L in LUAD.</div></div><div><h3>Methods</h3><div>We analyzed RNA sequencing data from The Cancer Genome Atlas (TCGA) LUAD cohort and normal lung tissues from the Genotype-Tissue Expression (GTEx) project to quantify tumor-specific NOC4L expression. Functional enrichment analysis employing Gene Ontology and KEGG pathways revealed associations with ribosome biogenesis, cell cycle regulation, and transcriptional dysregulation. Single-cell RNA analysis were interrogated to identify cellular subpopulations with elevated NOC4L expression. Immune microenvironment alterations were evaluated using ssGSEA algorithms, while methylation aberrations were mapped via MethSurv. The STarBase database and prognostic model were utilized to construct competing endogenous RNA (ceRNA) networks regulating NOC4L. siRNA mediated NOC4L knockdown in A549 and H1299 LUAD cell lines was performed to assess phenotypic impacts through CCK-8 proliferation assays, colony formation analyses, and migration experiments.</div></div><div><h3>Results</h3><div>NOC4L exhibited significant overexpression in LUAD compared to normal tissues (P &lt; 0.001), correlating with advanced TNM staging. Enrichment analysis indicated that NOC4L is associated with key pathways involved in cancer development. Single-cell analysis localized NOC4L overexpression predominantly within fibroblast subpopulations (c-9 cluster). High NOC4L expression correlated with immune microenvironment disorders, abnormal methylation levels, and mutations. Mechanistic studies identified the SNHG1/LINC00662-miR-101-3p axis as the predominant ceRNA regulator of NOC4L.</div><div>Functional silencing of NOC4L significantly inhibited the proliferation, clone formation, and migration abilities of LUAD cells.</div></div><div><h3>Conclusions</h3><div>NOC4L as an oncogenic protein promotes the cancer progression related to immune infiltrates, which underscores that NOC4L is a promising diagnostic and prognostic marker that may facilitate targeted therapies in LUAD.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100274"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145216487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Key determinants of the chemo-sensitizing activity of novel Telmisartan derivatives","authors":"Maximilian Gebhart ,&nbsp;Christian A. Elvert ,&nbsp;Anna M. Schoepf ,&nbsp;Alexandra Scheiber ,&nbsp;Stefan Schwaiger ,&nbsp;Cornelia A. Karg ,&nbsp;Ronald Gust ,&nbsp;Stefan Salcher","doi":"10.1016/j.ejmcr.2025.100281","DOIUrl":"10.1016/j.ejmcr.2025.100281","url":null,"abstract":"<div><div>Despite the success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML), resistance remains a major challenge due to target mutations and drug efflux. To counter this, chemo-sensitizers - non-cytotoxic agents that restore drug sensitivity - are being explored. A promising approach involves Telmisartan (<strong>1</strong>)-based cell death modulators, which may help overcome TKI resistance. Modification of the 2-COOH group of Telmisartan to a carboxamide (2-CONH₂, Telmiamide (<strong>2</strong>)) or methyl ester (2-CO₂CH₃, Telmiester (<strong>3</strong>)) transformed these derivatives into potent inhibitors of the efflux transporter ABCB1 and the STAT5 protein - two critical mediators of CML persistence during TKI therapy. Both compounds successfully restored Imatinib (<strong>Im</strong>) sensitivity in TKI-resistant CML cells. The present structure-activity relationship (SAR) analysis demonstrated that substituent modifications at 2-CONH₂ and 2-CO₂CH₃ significantly influenced biological efficacy, stability in cell culture medium, cellular uptake in CML cells, and inhibition of ABCB1 and STAT5. Among the tested compounds, propyl-, butyl-, phenyl-, and 4-phenoxyphenyl-substituted Telmiamides (<strong>2a-d</strong>) and Telmiesters (<strong>3a-d</strong>) exhibited strong chemo-sensitizing potential <em>in vitro</em>, with a half-maximal sensitizing concentration (SC₅₀) &lt; 0.5 μM. Additionally, most derivatives showed improved stability in cell culture, enhancing their suitability for future <em>in vivo</em> studies. When considering cellular uptake in CML cells, these compounds displayed ABCB1 inhibition comparable to the efflux transporter inhibitor Elacridar (<strong>E</strong>). Notably, their dual mode of action, combining potent ABCB1 and STAT5 inhibition with low cytotoxicity, offers a distinct advantage over Elacridar (<strong>E</strong>). ADME (absorption, distribution, metabolism, and excretion) studies identified significant limitations in the phenyl carboxamide derivative (<strong>2c</strong>), revealing low permeability and high metabolism due to the bound phenyl ring. These findings indicate that aromatic residues at the 2-CONH-R group may compromise bioavailability, highlighting a key structural constraint to address in the future optimization of Telmisartan derivatives for therapeutic development. Overall, the study highlights Telmisartan-based derivatives as promising candidates for overcoming TKI resistance in CML and warrants further optimization for clinical translation.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100281"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144563101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Opportunities for protein kinase drug discovery – 2025 update on the chemically underexplored human kinome","authors":"Selina Koch ,&nbsp;Elena Kullmann ,&nbsp;Jürgen Bajorath","doi":"10.1016/j.ejmcr.2025.100305","DOIUrl":"10.1016/j.ejmcr.2025.100305","url":null,"abstract":"<div><div>As a part of the Illuminating the Druggable Genome initiative, the U.S. National Institutes of Health (NIH), identified 162 understudied human protein and lipid kinases forming the “dark” kinome. In protein kinase (PK) drug discovery, the dark kinome has become a focal point in the search for new PK targets with interesting disease biology and lack of high-quality PK inhibitors (PKIs) for therapeutic intervention. Major criteria for the identification of dark kinases applied by the NIH included the lack of functional information and reagents for functional studies. We have previously introduced an alternative chemistry-centric assessment of understudied PKs that was based on a detailed analysis of the PKI coverage of the human kinome. This concept made it possible to differentiate between PKs based of their degree of chemical exploration. Given the continuing growth of PKI data in the public domain, we have repeated the analysis of chemically explored, underexplored, and unexplored PKs and updated the previous PK classification. As a part of our study, all PK and PKI data curated for our analysis are made publicly available together with the up-to-date chemical exploration-based PK classification and its comparison to the dark kinome. The curated data and kinome classification should be a useful resource for PK target prioritization and medicinal chemistry.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"15 ","pages":"Article 100305"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145412591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural optimization of indolizinoindolones to obtain potent new antimalarials with dual stage activity","authors":"Paulo A.F. Pacheco ,&nbsp;Ricardo J.F. Ferreira ,&nbsp;Diana Fontinha ,&nbsp;Caroline Conceição Sousa ,&nbsp;Jenny Legac ,&nbsp;Valentina Barcherini ,&nbsp;Philip J. Rosenthal ,&nbsp;Miguel Prudêncio ,&nbsp;Diogo R.M. Moreira ,&nbsp;Maria M.M. Santos","doi":"10.1016/j.ejmcr.2025.100258","DOIUrl":"10.1016/j.ejmcr.2025.100258","url":null,"abstract":"<div><div>Malaria continues to represent a major public health concern due to the emergence of resistance to most available drugs. We report the optimization of the indolizinoindolone scaffold to increase activity against erythrocytic stages of <em>Plasmodium</em> (<em>P.</em>) <em>falciparum</em> and against hepatic stages of the rodent parasite <em>P. berghei</em>. Twenty-six enantiopure indolizinoindolones were synthesized, with IC₅₀ values in the low micromolar and sub-micromolar range against both stages, and no significant cytotoxicity against mammalian cell lines. The most active compound showed nanomolar activity against <em>P. falciparum</em> blood stages <em>in vitro</em>, low micromolar activity against hepatic <em>P. berghei</em> infection <em>in vitro</em>, and a 7-fold higher selectivity index than that of chloroquine. This compound was also tested in <em>P. berghei</em>-infected mice, inhibiting the development of parasitemia relative to untreated mice. Overall, we identified a new set of lead antimalarial compounds. Further optimization of the pharmacokinetic properties of this scaffold is warranted.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"14 ","pages":"Article 100258"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benzo[b]thiophene-based 5-lipoxygenase inhibitors: A comprehensive review of therapeutic advances","authors":"Muhammed Jamshad Kongath ,&nbsp;Ameena Salim","doi":"10.1016/j.ejmcr.2025.100261","DOIUrl":"10.1016/j.ejmcr.2025.100261","url":null,"abstract":"<div><div>Heterocyclic compounds have an irreplaceable position in medicinal chemistry. Almost all bioactive natural products have heteroatoms in their active components. Benzo[b]thiophene is one of the important compounds among them. Several drugs contain benzo[b]thiophene as a potential portion responsible for pharmacological action. Zileuton, a potential 5-LOX inhibitor, is such a compound, having a benzo[b]thiophene ring as a crucial structural feature. Some of the previous research works revealed that a major side effect of zileuton is hepatotoxicity, which is found to be due to the presence of N-hydroxyurea attached to the benzo[b]thiophene ring. In this review article, we performed a systematic review of previous works for structural modification on the benzo[b]thiophene ring to improve its biological activity against the 5-LOX enzyme. Also, we compared the structure and biological activity and conducted a brief study of the structural activity relationship of the benzo[b]thiophene ring against the 5-LOX enzyme. Finally, we concluded that some positions of the benzo[b]thiophene ring are literally prone to an increase in 5-LOX inhibition after substituting with privileged motifs. So, substitution on the benzo[b]thiophene ring is able to develop much better 5-LOX inhibitors in the future.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"14 ","pages":"Article 100261"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143696907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-cancer potential of non-curcuminoid bioactive from Curcuma caesia Roxb. (Black Turmeric): Targeting cervical cancer via PI3K/Akt pathway modulation","authors":"Bishnu P. Parida ,&nbsp;Megha Radhakrishnan ,&nbsp;Varsha Goyal ,&nbsp;Astha Sharma ,&nbsp;Rupesh Zarekar ,&nbsp;Mumtaz A. Ansari ,&nbsp;Jasmeet Singh ,&nbsp;Sunita Singh ,&nbsp;Gopeshwar Narayan","doi":"10.1016/j.ejmcr.2025.100273","DOIUrl":"10.1016/j.ejmcr.2025.100273","url":null,"abstract":"<div><div><em>Curcuma caesia</em>, or black turmeric, is a significant medicinal plant used in traditional Indian medicine, including Ayurveda and folk practices. Indigenous communities in the northern Indo-Gangetic plains have utilized it for its analgesic, anti-inflammatory, and anti-infective properties. However, the anti-cancer potential of non-curcuminoid bioactive from <em>Curcuma caesia</em> remains underexplored. The current study investigates the anti-cancer potential of non-curcuminoid bioactive compounds derived from <em>Curcuma caesia</em> rhizome extracts, focusing on their effects against cervical cancer.</div><div>Using high-resolution mass spectrometry (HRMS), key compounds were identified from hexane (HECC) and methanolic (MECC) extracts, among which 3,4-dihydrocoumarin and (+)-ar-turmerone were prominent. <em>In vitro</em> cytotoxicity assays demonstrated that both HECC and MECC selectively inhibited the viability of cervical cancer cell lines, sparing non-tumorigenic HEK293T cells. Mechanistic analyses revealed that 3,4-dihydrocoumarin treatment led to mitochondrial membrane hyperpolarization, suppression of intracellular ROS, and cell cycle arrest at subG1 and G1 phases, while (+)-ar-turmerone had antagonistic modulatory effects. Western blotting confirmed downregulation of PI3K and Akt protein expression. Complementary ADME profiling indicated favorable pharmacokinetic properties, while molecular docking supported strong binding affinity of 3,4-dihydrocoumarin to PI3K and Akt targets, reinforcing its mechanism of action.</div><div><em>Curcuma caesia</em> rhizome fractions, especially 3,4-dihydrocoumarin, exhibit anti-cancer properties by modulating key molecular pathways, including the PI3K/Akt pathway.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"14 ","pages":"Article 100273"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144088809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zuogui Wan attenuates ovariectomy-induced osteoporosis via the GH/IGF1 axis and related pathways","authors":"Yujie Ma ,&nbsp;Pei Li ,&nbsp;Changheng Song ,&nbsp;Yuhan Wang ,&nbsp;Qiqi Yan ,&nbsp;Ying Yang ,&nbsp;Wenjie Li ,&nbsp;Xinyu Wan ,&nbsp;Ruyuan Zhu ,&nbsp;Jiayi Ma ,&nbsp;Yanjing Chen ,&nbsp;Haixia Liu ,&nbsp;Zhiguo Zhang","doi":"10.1016/j.ejmcr.2025.100264","DOIUrl":"10.1016/j.ejmcr.2025.100264","url":null,"abstract":"<div><h3>Introduction</h3><div>Zuogui Wan (ZGW)—one of the classic Chinese formulas—is clinically used to treat osteoporosis (OP). The current investigation aimed to analyze the phytochemical profile of ZGW and to elucidate its mechanisms of action in counteracting OP induced by ovariectomy (OVX) in rats.</div></div><div><h3>Methods</h3><div>The UPLC-MS/MS method was employed to determine the unique qualitative profile of the compounds. OVX rats were subjected to ZGW treatment for 12 weeks. Changes in body weight and bone protective effects were evaluated using various assays, including Vaginal smear assay, HE staining, Micro-CT imaging, and biomechanical testing. The related genes and proteins were validated using RT-qPCR, IHC, and Western blot.</div></div><div><h3>Results</h3><div>The UPLC-MS/MS analysis identified 2091 compounds, and the integral correction diagram showed 23 metabolites. ZGW treatment effectively ameliorated the diminished bone mineral density and compromised bone microstructures observed in OVX rats. Furthermore, ZGW administration to OVX rats increased bone tissue expression levels of RUNX2, BMP2, OSX, OC, and OPG. Moreover, ZGW administration in OVX rats restored the disturbed GH/IGF1 axis. Also, it activated PI3K/AKT signaling pathway and YAP/TAZ signaling pathway.</div></div><div><h3>Conclusion</h3><div>ZGW may exert its anti-OP effects by regulating the GH/IGF1 axis and its related signaling pathways.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"14 ","pages":"Article 100264"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143850133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Late-stage functionalization of anticancer agent Daniquidone and the in vitro anticancer activities of the derivatives","authors":"Geshuyi Chen ,&nbsp;Yechun Zeng ,&nbsp;Xin Chen ,&nbsp;Zhe Chang ,&nbsp;Pei Yuan ,&nbsp;Haijia Chen ,&nbsp;Yongxiu Yang ,&nbsp;Xiaolei Liang ,&nbsp;Kun Yue ,&nbsp;Depeng Zhao","doi":"10.1016/j.ejmcr.2025.100269","DOIUrl":"10.1016/j.ejmcr.2025.100269","url":null,"abstract":"<div><div>Nitrogen heterocycles play an important role in drugs and natural products. C-H late-stage functionalization (LSF) of N-heterocycles might provide a direct route to construct diversified analogues with potential pharmaceutical activities. Here, we employed a Cu-catalyzed C–H LSF to modify an anticancer drug Daniquidone and successfully converted the N-α position C–H bond into C–O, C–C and C–S bonds. Anticancer activities of all modified compounds <em>in vitro</em> were measured against three cell lines. The results showed that compound <strong>2i</strong> was the most active compound among all derivatives synthesized (IC₅₀ = 2.14 ± 1.23 μM against OVCAR-3, IC₅₀ = 4.07 ± 1.09 μM against A2780), <strong>1b</strong>, <strong>1g</strong> and <strong>2j</strong> also exhibit increased activity compared to the parent drug Daniquidone. Besides, molecular docking simulations with <strong>1b</strong>, <strong>1g</strong> and <strong>2j</strong> were conducted to further understand their binding modes.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"14 ","pages":"Article 100269"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143844232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reversing TGF-β1-induced fibrotic phenotype in human lung fibroblasts using a PROTAC tool derived from an indoline-based HDAC6 inhibitor","authors":"Ilaria Cursaro ,&nbsp;Valerio Ciccone ,&nbsp;Valeria Tudino ,&nbsp;Chiara Papulino ,&nbsp;Laura Scalvini ,&nbsp;Sandra Donnini ,&nbsp;Lucia Morbidelli ,&nbsp;Luca Bini ,&nbsp;Claudia Landi ,&nbsp;Chiara Contri ,&nbsp;Silvia Pasquini ,&nbsp;Fabrizio Vincenzi ,&nbsp;Katia Varani ,&nbsp;Alessio Lodola ,&nbsp;Marco Mor ,&nbsp;Rosaria Benedetti ,&nbsp;Lucia Altucci ,&nbsp;Stefania Butini ,&nbsp;Gabriele Carullo ,&nbsp;Sandra Gemma ,&nbsp;Giuseppe Campiani","doi":"10.1016/j.ejmcr.2025.100276","DOIUrl":"10.1016/j.ejmcr.2025.100276","url":null,"abstract":"<div><div>Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating interstitial lung disease characterized by limited therapeutic options, with only two FDA-approved palliative agents currently available. Given its poor prognosis and the high incidence of lung transplantation, there is a pressing need to develop innovative and effective therapeutics. Histone deacetylase 6 (HDAC6) has been identified as a key driver of fibrotic progression in IPF, and selective inhibitors of this isoform were able to revert the fibrotic phenotypes. Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that can trigger the degradation of a specific target in cells, including HDAC6 enzyme. Therefore, the application of PROTAC technology may represent a novel therapeutic strategy for IPF. We showcase the design, synthesis, and biological evaluation of a library of first-in-class antifibrotic HDAC6-targeting PROTACs, incorporating our <em>in-house</em> inhibitor <strong>1</strong> as the HDAC6 ligand. Newly developed PROTACs <strong>5a</strong> and <strong>5c</strong> showed effective degradation of HDAC6 in A549 lung cells and IMR-90 lung fibroblasts. <strong>5a</strong> and <strong>5c</strong> exhibited significant antifibrotic effects against the TGF-β1 induced fibrotic phenotype on IMR-90 cells, a model that mimics IPF conditions. The generation of putative ternary complexes involving PROTAC molecules, the E3-ligase cereblon (CRBN) and the HDAC6 target protein was supported by molecular modelling techniques, including protein-protein docking and molecular dynamics simulations. Mechanistic investigations, based on pull-down experiments, confirmed that the newly synthetized compounds were able to reduce HDAC6 levels through a proteasome- and CRBN-dependent mechanism as confirmed by experiments with neddylation and proteasome inhibitors. This pioneering exploration of targeted protein degradation in IPF-like conditions provides compelling evidence of its therapeutic promise, paving the way for a broader application of PROTACs in treating rare diseases.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"14 ","pages":"Article 100276"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144134767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondria-targeting phosphonium salts of monensin A as the source of novel antiproliferative agents","authors":"Michał Sulik ,&nbsp;Marta Jędrzejczyk ,&nbsp;Magdalena Mielczarek-Puta ,&nbsp;Gwan Yong Lim ,&nbsp;Małgorzata Podsiad ,&nbsp;Jakub Hoser ,&nbsp;Piotr Bednarczyk ,&nbsp;Marta Struga ,&nbsp;Adam Huczyński","doi":"10.1016/j.ejmcr.2025.100275","DOIUrl":"10.1016/j.ejmcr.2025.100275","url":null,"abstract":"<div><div>Monensin A is a representative of natural ionophores, which exhibit a broad spectrum of biological properties, with the most fascinating being its potent anticancer activity. A very intriguing research direction is the rational chemical modification of the monensin A skeleton to obtain analogs with higher antiproliferative activity and selectivity indices. In this paper, synthetic access to monensin A conjugates with mitochondria-targeting chemical moieties, such as the triphenylphosphonium cation and its analogs, is presented. Furthermore, the obtained derivatives were screened for lead structures with improved anticancer properties and mitochondria-targeting ability. Some of the obtained compounds exhibited greater antiproliferative activity and selectivity than unmodified monensin. Furthermore, biological and biophysical studies have confirmed that the induction of apoptosis by the aforementioned hybrids is linked to targeting of mitochondria in cancer cells. These results prove that such a strategy is a promising approach for the search for new effective drug candidates.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"14 ","pages":"Article 100275"},"PeriodicalIF":0.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144134766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}