Bioorganic & Medicinal Chemistry最新文献

{"title":"Research progress of flavonoids targeting estrogen receptor in the treatment of breast cancer","authors":"Jianling Long ,&nbsp;Pengju Ye ,&nbsp;Weixi Yuan ,&nbsp;Qixian Yang ,&nbsp;Zhe Wang ,&nbsp;Hongxiang Xiao ,&nbsp;Zhizhong Xie ,&nbsp;Xiaoyong Lei ,&nbsp;Xiaoyan Yang ,&nbsp;Xiangping Deng ,&nbsp;Guotao Tang","doi":"10.1016/j.bmc.2025.118106","DOIUrl":"10.1016/j.bmc.2025.118106","url":null,"abstract":"<div><div>Breast cancer (BC) stands as the most prevalent malignancy among women. Targeting the estrogen receptor (ER) or ER pathway is one of the important approaches for ER⁺ BC treatment. As a class of phytoestrogens, flavonoids possess notable anti-tumor properties and hold immense potential in regulating ER signaling. In this review, we reported the recent advances in both <em>in vitro</em> and <em>in vivo</em> studies of flavonoids and their synthetic derivatives targeting the ER signaling pathway, including the target and mechanism of action of these molecules, as well as their structure–activity relationship. Based on the available literature, the beneficial effects of flavonoids as ER targeting agents are promising but they require further <em>in vitro</em> and <em>in vivo</em> studies to enable its translation from bench to bedside. This review will provide valuable guidance and insights for the future development of drugs targeting the ER pathway.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118106"},"PeriodicalIF":3.3,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143378045","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":"Rational design and synthesis of pyrazole derivatives as potential SARS-CoV-2 Mpro inhibitors: An integrated approach merging combinatorial chemistry, molecular docking, and deep learning","authors":"Arthur Antunes Ferrarezi ,&nbsp;João Vítor Perez de Souza ,&nbsp;Bernard Maigret ,&nbsp;Érika Seki Kioshima ,&nbsp;Sidnei Moura ,&nbsp;Arildo José Braz de Oliveira ,&nbsp;Fernanda Andreia Rosa ,&nbsp;Regina Aparecida Correia Gonçalves","doi":"10.1016/j.bmc.2025.118095","DOIUrl":"10.1016/j.bmc.2025.118095","url":null,"abstract":"<div><div>The global impact of SARS-CoV-2 has highlighted the urgent need for novel antiviral therapies. This study integrates combinatorial chemistry, molecular docking, and deep learning to design, evaluate and synthesize new pyrazole derivatives as potential inhibitors of the SARS-CoV-2 main protease (M^pro). A library of over 60,000 pyrazole-based structures was generated through scaffold decoration to enhance chemical diversity. Virtual screening employed molecular docking (ChemPLP scoring) and deep learning (DeepPurpose), with consensus ranking to identify top candidates. Binding free energy calculations refined the selection, revealing critical structural features such as tryptamine and <em>N</em>-phenyl fragments for M^pro binding. High-temperature solvent-free amidation allowed the synthesis of a selected derivative. Final compounds demonstrated favorable drug-likeness properties based on Lipinski’s and Veber’s rules. This work highlights the integration of computational and synthetic strategies to accelerate the discovery of M^pro inhibitors and provides a framework for future antiviral development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118095"},"PeriodicalIF":3.3,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143372381","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":"Design, Synthesis and Biological Evaluation of 2-Phenyl Indole Analogues of OXi8006 as Colchicine Site Inhibitors of Tubulin Polymerization and Vascular Disrupting Agents","authors":"Rebecca Vairin ,&nbsp;Caleb Tamminga ,&nbsp;Zhe Shi ,&nbsp;Christian Borchardt ,&nbsp;Jayaram Jambulapati ,&nbsp;Ruoli Bai ,&nbsp;Hashini Wanniarachchi ,&nbsp;Lorena Bueno ,&nbsp;Ernest Hamel ,&nbsp;Ralph P. Mason ,&nbsp;Mary Lynn Trawick ,&nbsp;Kevin G. Pinney","doi":"10.1016/j.bmc.2024.117981","DOIUrl":"10.1016/j.bmc.2024.117981","url":null,"abstract":"<div><div>Inhibitors of tubulin polymerization represent a promising therapeutic approach for the treatment of solid tumors. Molecules that bind to the colchicine site are of interest as they can function with a dual mechanism of action as both potent antiproliferative agents and tumor-selective vascular disrupting agents (VDAs). One such example is a 2-aryl-3-aroyl-indole molecule (OXi8006) from our laboratory that demonstrates potent inhibition of tubulin polymerization and strong antiproliferative activity (cytotoxicity) against a variety of human cancer cell lines. A water-soluble prodrug OXi8007, synthesized from OXi8006, demonstrates <em>in vivo</em> disruption of tumor-associated microvessels in several tumor types (mouse models). The molecular framework of OXi8006 inspired a series of fourteen new 2-aryl-3-aroyl-indole analogues that incorporated various functional group modifications on both the indole core and the aroyl ring. Electron withdrawing and donating groups at the mono-substituted 3′ position and the di-substituted 3′,5′ positions were all accommodated while maintaining inhibition of tubulin polymerization (IC₅₀ &lt; 5 μM), with several analogues demonstrating activity comparable to OXi8006 and the benchmark natural product combretastatin A-4 (CA4). Preliminary structure–activity relationship (SAR) studies were further enhanced by molecular docking to predict possible colchicine site interactions. Two analogues (KGP366 and KGP369) previously synthesized in our laboratory were re-synthesized using a somewhat modified route to increase synthetic efficiency and were subsequently converted to their corresponding water-soluble phosphate prodrug salts to evaluate their efficacy as VDAs. Administration of the prodrug salt (KGP415) of KGP369 caused significant reduction in bioluminescence signal from an orthotopic kidney tumor (RENCA-luc) in BALB/c mice, indicative of VDA activity. Collectively, these new functionalized indole-based analogues have extended SAR knowledge related to the colchicine binding site, and the most biologically active analogues hold promise for continued development as pre-clinical candidates for cancer therapy.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"Article 117981"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816628","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":"Charge-neutralized polyethylenimine-lipid nanoparticles for gene transfer to human embryonic stem cells","authors":"Guoqing Feng ,&nbsp;Yang Bai ,&nbsp;Pengyu Huang ,&nbsp;Yuan Liu ,&nbsp;Qingbin Yang ,&nbsp;Bowen Li ,&nbsp;Qing Yuan ,&nbsp;Niansong Qian ,&nbsp;Bin Zheng","doi":"10.1016/j.bmc.2024.118008","DOIUrl":"10.1016/j.bmc.2024.118008","url":null,"abstract":"<div><div>Gene delivery is fundamentally crucial for the genetic manipulation of stem cells. Here, we present a straightforward approach to create a library of charge-neutralized polyethylenimine (PEI)-lipid nanoparticles designed for stem cell transfection. These lipid nanoparticles were formulated using small, branched PEI and lipidic anhydrides. Remarkably, over 15% of the lipid nanoparticles demonstrated high transfection efficiency across various cell types, surpassing the efficiency of both Lipofectamine 2000 and FuGENE HD. A structure–activity analysis indicated that the length and ratio of hydrophobic alkyl substitutions were critical parameters for efficient gene delivery. Notably, the transfection efficiency was higher than that of the original cation PEI. Our optimized PEI-lipid system enabled highly effective plasmid DNA delivery and successfully co-transferred two plasmid DNAs into difficult-to-transfect human embryonic stem cells (hESCs), facilitating optogenetic manipulation within these cells.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"Article 118008"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783437","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":"Potential COX-2 inhibitors modulating NF-κB/MAPK signaling pathways: Design, synthesis and evaluation of anti-inflammatory activity of Pterostilbene-carboxylic acid derivatives with an oxime ether moiety","authors":"Peng Luo ,&nbsp;Taotao Chen ,&nbsp;Shaoling Huang ,&nbsp;Feng Peng ,&nbsp;Yunhou Huang ,&nbsp;Weigao Pan","doi":"10.1016/j.bmc.2024.118022","DOIUrl":"10.1016/j.bmc.2024.118022","url":null,"abstract":"<div><div>In this work, a series of novel Pterostilbene–oxime ether–carboxylic acid (<strong>POC</strong>) derivatives (<strong>d1–d10</strong>, <strong>e1–e10</strong> and <strong>1</strong>–<strong>13</strong>) were designed, synthesized, and characterized by spectroscopic techniques. In order to further determine the absolute configuration of these compounds, one of them, compound <strong>d3</strong>, was investigated by X-ray single crystal diffraction method. <strong>d3</strong> had a triclinic crystal with <em>P</em>-1 space group, and its <img>CH<img>CH<img> and <img>CH<img>N<img> was confirmed as <em>E</em> configuration. A strong hydrogen bond was formed between the hydrogen atom in <img>CH<img>CH<img> moiety and the nitrogen atom in <img>CH<img>N<img> moiety, which was a vital factor in the formation and stability of <em>E</em> configuration in the <img>CH<img>CH<img> and <img>CH<img>N<img>. The safety and anti-inflammatory activities of compounds (<strong>d1–d10</strong>, <strong>e1–e10</strong> and <strong>1</strong>–<strong>13</strong>) in vitro were evaluated. At 20 μM, compounds (<strong>d1–d10</strong>, <strong>e1–e10</strong> and <strong>1</strong>–<strong>13</strong> were non-toxic and exhibited weak to strong inhibitory effects on the LPS-induced NO release. Among them, five compounds (<strong>1</strong>, <strong>2</strong>, <strong>7</strong>, <strong>8</strong> and <strong>9</strong>) showed excellent anti-inflammatory effects with IC₅₀ (NO) values ranging from 9.87 to 19.78 μM, as well as strong COX-2 inhibitory abilities with IC₅₀ (COX-2) values ranging from 85.44 to 140.88 nM. Moreover, there was a rough positive correlation between their anti-inflammatory properties and the COX-2 inhibitory abilities. Compounds (<strong>1</strong>, <strong>2</strong>, <strong>7</strong>, <strong>8</strong> and <strong>9</strong>) smoothly docked with COX-2 protein (PDB ID: 5KIR) to form stable complexes with strong hydrogen bonds, with an affinity range of −8.3 to −9.9 kcal/mol. SAR indicated that the amidation of POC at R₂ position was more favorable for enhancing the compound’s biological actives than esterification. In addition, the 4-fluobenzyl substitution at R₂ position of the oxime ether moiety can obviously enhance the activity of above amide derivates. Introducing acyl groups (<img>CO(CH₂)_nCH₃, n = 2, 4 and 6) into <img>NH(CH₂)₃OH group to form ester chain is disadvantageous for activity enhancing, moreover, the longer the carbon chain, the poorer the activity. The strongest COX-2 inhibitor (IC₅₀ (COX-2) = 85.44 ± 3.88 nM), compound <strong>7</strong>, exerted as anti-inflammatory activities (IC₅₀ (NO) = 9.87 ± 1.38 μM) by down-regulating the expression of COX-2 and iNOS, and modulating NF-κB/MAPK signaling pathways.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"Article 118022"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790512","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 in vitro evaluation of novel compounds and discovery of a promising iodine-125 radioligand for purinergic P2X7 receptor (P2X7R)","authors":"Lin Qiu ,&nbsp;Jinzhi Wang ,&nbsp;Manju Tewari ,&nbsp;Derek T. Rensing ,&nbsp;Terrance M. Egan ,&nbsp;Joel S. Perlmutter ,&nbsp;Zhude Tu","doi":"10.1016/j.bmc.2024.118054","DOIUrl":"10.1016/j.bmc.2024.118054","url":null,"abstract":"<div><div>The purinergic P2X ligand-gated ion channel 7 receptor (P2X7R) plays a critical role in various inflammatory processes and other diseases. Fast determination of compounds P2X7R binding potency and discovery of a promise PET radiotracer for imaging P2X7R require a P2X7R suitable radioligand for radioactive competitive binding assay. Herein, we designed and synthesized thirteen new P2X7R ligands and determined the <em>in vitro</em> binding potency. The fluorescence screening assay identified the iodide compound <strong>1c</strong> with high potency and specificity toward P2X7R with an IC₅₀ of 0.25 ± 0.05 nM. Therefore, <strong>1c</strong> was ¹²⁵I-labeled to afford [¹²⁵I]<strong>1c</strong> with a good radiochemical yield (44 ± 12 %, n = 3) and high radiochemical purity (&gt;95 %). Radioligand saturation binding assay showed that [¹²⁵I]<strong>1c</strong> specifically bound to human P2X7R with high affinity (K_d = 1.68 nM and B_max = 94 fmol/mg). A radioactive high throughput binding assay using [¹²⁵I]<strong>1c</strong> for our new compounds demonstrated that the imidazole compounds <strong>1b</strong>, <strong>1c</strong>, and <strong>1d</strong> exhibited high inhibition for &gt;70 %, while the analogues of <strong>GSK314181A</strong> exhibited low inhibition for &lt;35 %. In addition, our radioligand competitive binding assays using [¹²⁵I]<strong>1c</strong> demonstrated that <strong>1b</strong>, <strong>1c</strong>, and <strong>1d</strong> have high potency with IC₅₀ values of 7.91 ± 0.22, 7.06 ± 1.68, and 7.16 ± 0.41 nM toward P2X7R, respectively.Together, compounds <strong>1b</strong>, <strong>1c</strong>, and <strong>1d</strong> are highly potent for P2X7R, and [¹²⁵I]<strong>1c</strong> has great potential to be a radioligand for screening P2X7R binding potency of the new compounds and investigating the P2X7R expression in animal models of human disease.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"Article 118054"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142908824","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":"Synthetic glycol-split heparin tri- and tetrasaccharides provide new insights into structural peculiarities for antiheparanase activity","authors":"Minghong Ni ,&nbsp;Michela Parafioriti ,&nbsp;Emiliano Esposito ,&nbsp;Margherita Danzi ,&nbsp;Ornela Cano ,&nbsp;Laura Muzi ,&nbsp;Yasmin Kayal ,&nbsp;Vito Ferro ,&nbsp;Israel Vlodavsky ,&nbsp;Stefano Elli ,&nbsp;Annamaria Naggi ,&nbsp;Maurice Petitou ,&nbsp;Marco Guerrini","doi":"10.1016/j.bmc.2024.118052","DOIUrl":"10.1016/j.bmc.2024.118052","url":null,"abstract":"<div><div>Heparanase is the only known <em>endo</em>-β-glucuronidase able to cleave heparan sulfate, participating in degradation and remodelling of the extracellular matrix. Heparanase upregulation promotes tumor growth and metastasis, therefore, its inhibition is a target for anticancer therapies. Heparan sulfate mimetics bearing glycol-split (gs) units are one of the most promising class of heparanase inhibitors. Herein we describe a total synthesis of two trisaccharides (MeO-GlcNS6S-IdoA/GlcA-GlcNS6S-OMe) differing in epimeric uronic acid residues and one tetrasaccharide (MeO-IdoA-GlcNS6S-IdoA-GlcNS6S-OMe), together with their corresponding glycol-split versions, prepared by periodate oxidation and further modified either via reduction or Pinnick oxidation to obtain gs or tricarboxylated saccharides. An intermediate imine was observed during periodate oxidation, which causes formation of byproducts. Evaluation of the heparanase inhibitory activity showed that the glycol-split trisaccharides were more potent than their intact uronic acid congeners. The binding interactions of the glycol-split trisaccharides with heparanase were investigated by a combined STD NMR and molecular docking approach, with good agreement obtained between the STD NMR experimental data, docking calculations and the in vitro activity results, helping to rationalize the observed inhibition data<strong>.</strong></div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"Article 118052"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913157","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":"Tc-99m labeled PSMA-617 as a potential SPECT radiotracer for prostate cancer diagnostics: Complexation optimization and its in vitro/vivo evaluation","authors":"Kalapaphuk Tachatumvitoon ,&nbsp;Charasphat Preuksarattanawut ,&nbsp;Thititip Tippayamontri ,&nbsp;Piyachai Khomein","doi":"10.1016/j.bmc.2024.118058","DOIUrl":"10.1016/j.bmc.2024.118058","url":null,"abstract":"<div><div>Technetium-99m (Tc-99m) is the most employed radionuclide in nuclear imaging diagnostics worldwide for many diseases. The ideal physiochemical properties of Tc-99m (such as half-life and pure gamma energy) make it favorable for Single Photon Emission Computed Tomography (SPECT). In this study, we aim to expand the utilization of Tc-99m radiopharmaceutical toward prostate cancer diagnostics which is currently no FDA approved products and has been intensively examined for a potential candidate. The new formulation for Tc-99m complexation with PSMA-617, a current ligand for radionuclide therapy of prostate cancer with lutetium-177 (Lu-177), has been investigated. Co-complexation with citrate was utilized to improve the labeling efficiency by over 97 %. The stability of the new radiopharmaceutical was in vitro evaluated confirming that the Tc-99m labeled PSMA-617 remained stable for over a single half-life of Tc-99m in normal saline solution and in human serum. The in vivo study in the LNCaP xenografted mouse model confirmed a high selectivity of the new tracer toward prostate cancer.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"Article 118058"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925862","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":"Discovery of novel xanthohumol C derivatives regulating XRCC2 transcription and expression for the treatment of colorectal cancer","authors":"Qianqian Zhu ,&nbsp;Mengying Wang ,&nbsp;Yan Wang ,&nbsp;Bin Li ,&nbsp;Jiahao Zheng ,&nbsp;Yina Hu ,&nbsp;Changgui Shi ,&nbsp;Dalong Wang ,&nbsp;Di Cao ,&nbsp;Zhiguo Liu ,&nbsp;Xiaohui Zheng ,&nbsp;Kun Wang","doi":"10.1016/j.bmc.2024.118048","DOIUrl":"10.1016/j.bmc.2024.118048","url":null,"abstract":"<div><div>X-ray repair cross-complementing 2 (XRCC2), a critical protein in homologous recombination (HR), plays a significant role in the occurrence, progression, and drug resistance of colorectal cancer (CRC). In this study, a series of xanthohumol C derivatives were synthesized, and their anticancer activity was evaluated. The results revealed that <strong>A33</strong> demonstrated the potent anticancer activity and effectively inhibited the proliferation of CRC cells <em>in vitro</em>. Mechanistic investigations revealed that <strong>A33</strong> suppressed the transcription and expression of XRCC2, resulting in cell cycle delay and the accumulation of DNA damage, ultimately leading to cell proliferation inhibition. Furthermore, <strong>A33</strong> displayed high safety, favorable bioavailability (<em>F</em> = 37.51 %), and potent tumor growth inhibition <em>in vivo</em>, which highlighting its potential as a candidate for the development of novel anti-CRC therapies.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"Article 118048"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142890848","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":"An overview of GPX4-targeting TPDs for cancer therapy","authors":"Xiaojuan Yang ,&nbsp;Liqiang Wu ,&nbsp;Shaohong Xu","doi":"10.1016/j.bmc.2024.118046","DOIUrl":"10.1016/j.bmc.2024.118046","url":null,"abstract":"<div><div>Ferroptosis is a newly identified form of regulated, non-apoptotic cell death caused by iron-dependent phospholipid peroxidation. Glutathione peroxidase 4 (GPX4) inactivation-induced ferroptosis is an efficient antitumor treatment. Currently, several GPX4 inhibitors have been identified. However, these inhibitors exhibit low selectivity and poor pharmacokinetic properties that preclude their clinical use. Targeted protein degradation (TPD) is an efficient strategy for discovering drugs and has unique advantages over target protein inhibition. Given GPX4′s antitumor effects and the potential of TPD, researchers have explored GPX4-targeting TPDs, which outperform conventional inhibitors in several aspects, such as increased selectivity, strong anti-proliferative effects, overcoming drug resistance, and enhancing drug-like properties. In this review, we comprehensively summarize the progress in GPX4-targeting TPDs. In addition, we reviewed the changes and challenges related to the development of GPX4-targeting TPDs for cancer therapy.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"Article 118046"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851736","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}