Bioorganic & Medicinal Chemistry Letters最新文献

{"title":"Therapeutic potential of STK17A targeted therapies","authors":"Hafsa Ouaakki ,&nbsp;Eduardo Bravo Jr ,&nbsp;Justin Taylor ,&nbsp;Yangbo Feng","doi":"10.1016/j.bmcl.2025.130506","DOIUrl":"10.1016/j.bmcl.2025.130506","url":null,"abstract":"<div><div>STK17A (serine/threonine kinase 17a), also known as DRAK1 (death-associated protein kinase-related apoptosis-inducing protein kinase 1), is a member of the death-associated protein kinase (DAPK) family and acts as a positive regulator of apoptosis. STK17A is a dark kinase and is an understudied member in the DAPK family. Thus far, it has been found to serve a significant role in cell proliferation, apoptosis, tumor metastasis, and tumorigenesis. This review summarizes the structure of STK17A, its reported biological functions, and expression in cancer. Small molecule inhibitors for STK17A, including those specifically developed for STK17A and those designed for other kinases but also inhibit STK17A as an unintended target, are discussed. Finally, some outlooks for drug discovery regarding STK17A are described.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130506"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145754959","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":"Exploring the therapeutic potential of deuterated PPARγ agonists for NASH","authors":"Xudong Pang ,&nbsp;Dawei Cui ,&nbsp;Ruifeng Liu ,&nbsp;Binhua Lv ,&nbsp;Cheng-Yun Wang","doi":"10.1016/j.bmcl.2025.130489","DOIUrl":"10.1016/j.bmcl.2025.130489","url":null,"abstract":"<div><div>NASH represents an increasingly prevalent chronic liver disease, and TZDs are investigated as a potential therapeutic strategy. However, the inherent enolic structure of TZDs leads to enantiomeric instability and racemization, often requiring their use as racemic mixtures. We here report the development of a novel TZD-derivative, <strong>9</strong>, in which deuterium incorporation at the chiral center was strategically employed to enhance stereoisomeric stability while maintaining the desired pharmacological profile. In vitro, compound <strong>9</strong> displayed robust activity, with an EC₅₀ of 0.32 ± 0.04 μM in HEK293 cells. Pharmacokinetic analysis revealed a C_max of 1693 ± 339 ng/mL and an AUC_0-24h of 8711 ± 871 ng∙h/mL. Furthermore, compound <strong>9</strong> demonstrated superior therapeutic efficacy in a mouse model of NASH. These findings suggest that the compound <strong>9</strong> represents a promising therapeutic candidate for NASH.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130489"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145647004","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":"Identification of flavonoid-based small molecule inhibitors with dual-targeting capability against RdRp and Mpro of SARS-CoV-2","authors":"Yanlei Su ,&nbsp;Yujia Wang ,&nbsp;Jianyuan Zhao ,&nbsp;Keyu Guo ,&nbsp;Xuhong Duan ,&nbsp;Honghai Wu ,&nbsp;Dianxing Sun ,&nbsp;Jing Zhang ,&nbsp;Shan Cen","doi":"10.1016/j.bmcl.2025.130501","DOIUrl":"10.1016/j.bmcl.2025.130501","url":null,"abstract":"<div><div>Due to issues of high transmissibility, immune evasion, and drug resistance in SARS-CoV-2 variants, there is an urgent need for novel antiviral drugs. Plant-derived flavonoids such as baicalein (EC₅₀ = 4.5 μM) and baicalin (EC₅₀ = 9.0 μM) exhibit broad-spectrum antiviral potential <em>via</em> RNA-dependent RNA polymerase (RdRp) inhibition. Based on this, our study identified two derivatives through pharmacophore alignment between flavonoid scaffolds and the main protease (Mpro) inhibitor 13b: a psoralen-derived lignan (Comp.<strong>1</strong>) and a novel isoflavone analog (Comp.<strong>2</strong>), with dual-targeting capability against SARS-CoV-2 RdRp and Mpro. Computational docking elucidated the binding interactions of compounds with RdRp, Mpro, and the L50F/E166V double mutant Mpro. <em>In vitro</em> assays demonstrated that Comp.<strong>1</strong> exhibited micromolar-range inhibitory effects on both RdRp (EC₅₀: 25.45 μM) and Mpro (IC₅₀: 125.4 μM), outperforming Comp.<strong>2</strong>. Both compounds maintained inhibitory activity against the PF07321332-resistant L50F/E166V double mutant Mpro, with IC₅₀ fold-change values of 1.23 and 1.18, respectively, compared to an 8.62-fold reduction for PF07321332. However, ADMET evaluation indicated that although compounds met basic physicochemical criteria (including molecular weight, TPSA, and compliance with Lipinski's Rule of Five), they still presented critical toxicological liabilities, including high genotoxicity risk (Comp.<strong>1</strong>: 0.838 probability) and CYP3A4 inhibition (&gt;0.97), necessitating extensive structural optimization. This study confirms that flavonoid derivatives represent promising starting points for developing resistance-aware antiviral agents, though their current profiles classify them as early-stage leads requiring substantial optimization.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130501"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145719923","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 2-mercaptoquinazolinone N-hydroxycinnamamides as histone deacetylase inhibitors: design, synthesis, and anticancer evaluation","authors":"Le Thi Thao ,&nbsp;Hwa Kyung Kim ,&nbsp;Nguyen Phuong Ngan ,&nbsp;Bui Quang Cuong ,&nbsp;Dao Thi Kim Oanh ,&nbsp;Do Thi Mai Dung ,&nbsp;Da Hyeon Kang ,&nbsp;Ha Young Kim ,&nbsp;Eun Hye Song ,&nbsp;Jong Soon Kang ,&nbsp;Duong Tien Anh ,&nbsp;Truong Thanh Tung ,&nbsp;Sang-Bae Han ,&nbsp;Nguyen-Hai Nam","doi":"10.1016/j.bmcl.2025.130509","DOIUrl":"10.1016/j.bmcl.2025.130509","url":null,"abstract":"<div><div>Histone deacetylases (HDACs) are key therapeutic targets in oncology, and hydroxamic acid derivatives represent one of the most effective inhibitor classes. To explore the structure-activity relationships of this scaffold, a series of 2-mercaptoquinazoline-based hydroxamic acid derivatives (<strong>4a-e</strong>, <strong>7a-i</strong>, and <strong>10a-e</strong>) were synthesized and evaluated for HDAC inhibition and anticancer activity, with SAHA serving as a positive control. The <strong>4a-e</strong> series emerged as the most potent HDAC inhibitors, with IC₅₀ values of 0.33–0.87 μM, led by <strong>4a</strong> (0.33 ± 0.02 μM), though weaker than SAHA (0.06 ± 0.01 μM). Cytotoxicity assays across colorectal (SW620, HCT116), breast (MDA-MB-231), prostate (PC-3), and lung (A549) cancer cell lines demonstrated that <strong>4b</strong> (6-CH₃) and <strong>4c</strong> (7-CH₃) were the most effective, achieving IC₅₀ values of 0.93–1.34 μM in HCT116 and 1.79–2.08 μM in SW620. In the <strong>7a-i</strong> series, compounds <strong>7b</strong> (6-CH₃), <strong>7d</strong> (6-Cl), and particularly <strong>7f</strong> (7-F) demonstrated notable cytotoxicity with IC₅₀ values of 1.14–3.64 μM across SW620, HCT116, and MDA-MB-231 cells, comparable to the most active derivatives in the 4-series; conversely, bulky halogen substituents (<strong>7g</strong>, <strong>7i</strong>) or the unsubstituted analog <strong>7a</strong> led to markedly reduced activity (&gt; 4.5 μM). The <strong>10a-e</strong> series was significantly less active, and <strong>10e</strong> (7-F) showed undesirable toxicity toward normal MRC-5 fibroblasts (IC₅₀ = 0.72 ± 0.02 μM). Mechanistic studies further confirmed that <strong>4c</strong> and <strong>7f</strong> induced G₂/M arrest and apoptosis in SW620 cells. Collectively, these findings highlight <strong>4a-c</strong> and <strong>7f</strong> as promising lead compounds, combining submicromolar HDAC inhibition, potent antiproliferative effects, and acceptable selectivity, providing a strong foundation for further development of quinazoline-based HDAC inhibitors. Molecular docking studies supported these results by revealing favorable interactions of the hydroxamate zinc-binding group and the 2-mercaptoquinazoline scaffold within the HDAC active site, consistent with the observed structure-activity relationship (SAR) trends.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130509"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800137","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, and activity evaluation of alpinetin derivatives as potential anti-liver cancer drugs","authors":"Yanhui Yi ,&nbsp;Yupei Sun ,&nbsp;Xiangyang Zhang ,&nbsp;Jianzeng Xin ,&nbsp;Feng Zhao ,&nbsp;Wei Zhu ,&nbsp;Sheng Liu","doi":"10.1016/j.bmcl.2025.130482","DOIUrl":"10.1016/j.bmcl.2025.130482","url":null,"abstract":"<div><div>Liver cancer represents a major global health challenge, significantly impacting populations both in China and worldwide. Alpinetin (ALP), extracted from the ginger plant cardamom, has been shown to possess significant anti-liver cancer activity. However, its solubility and mechanism of action remain unclear, hindering its further development and application. Heat shock protein 70 (HSP70) has been proven to be a potential target for the treatment of liver cancer. Based on rational drug design principles, ALP was conjugated with specific pharmacophores through oxime linkages to yield novel compounds, aiming to reduce toxicity and enhanced activity. Thus, representative compounds 1a and 1b were obtained. Then, the preliminary mechanism of action was further investigated. Western blot analysis results indicate that compounds 1a and 1b could inhibit the expression of HSP70 protein in HepG2 liver cancer cells. Cell apoptosis data indicate that the synthesized compounds exert anticancer activity by inducing apoptosis. Therefore, this study suggests that ALP and its derivatives may become promising drugs for exerting anti liver cancer effects by regulating the expression of HSP70 protein.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130482"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145627313","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":"Synthesis of new Pyridazinone derivatives and their dual inhibitory activity on aldose reductase and α-glucosidase","authors":"Mevlüt Akdağ ,&nbsp;Merve Güneş Çam ,&nbsp;Derya Ergen ,&nbsp;Yeliz Demir ,&nbsp;Şükrü Beydemir ,&nbsp;Azime Berna Özçelik","doi":"10.1016/j.bmcl.2025.130498","DOIUrl":"10.1016/j.bmcl.2025.130498","url":null,"abstract":"<div><div>Diabetes mellitus is a chronic metabolic disorder associated with microvascular complications such as neuropathy, nephropathy, and retinopathy. Two complementary therapeutic strategies are targeting the polyol pathway <em>via</em> aldose reductase (ALR2) inhibition and controlling postprandial hyperglycemia through α-glucosidase (α-Glu) inhibition. In this study, we designed and synthesized a novel series of eight pyridazinone derivatives incorporating thiosemicarbazide, S-triazole, and 1,3,4-thiadiazole 2-amine scaffolds. These compounds were evaluated for their dual inhibitory potential against ALR2 and α-Glu enzymes using <em>in vitro</em> kinetic assays. Among the tested molecules, compound <strong>4</strong>, bearing a fluorinated thiadiazole moiety, exhibited the most potent activity with K_i values of 0.094 μM (ALR2) and 0.171 μM (α-Glu), surpassing standard inhibitors epalrestat and acarbose, respectively. Structure-activity relationship analysis indicated that fluorine substitution and a 1,3,4-thiadiazole core significantly enhance dual inhibitory potency. Docking studies further confirmed strong binding interactions within the active site of ALR2, supported by π–π stacking, hydrogen bonding, and hydrophobic interactions. These findings suggest that halogenated pyridazinone derivatives, especially fluorinated thiadiazole analogs, represent promising dual inhibitors for managing hyperglycemia and preventing diabetic complications. The dual-targeting approach demonstrated in this work offers a rational design framework for future antidiabetic drug development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130498"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145699488","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":"Synthesis and antitumor activity of derivatives of SKF-83566","authors":"Xiu-Jun Wang ,&nbsp;Meng-Xin Lu ,&nbsp;Qiu-yue Jin ,&nbsp;Zi-Yan Lang ,&nbsp;Ming-Li Yang ,&nbsp;Jing Ji","doi":"10.1016/j.bmcl.2025.130502","DOIUrl":"10.1016/j.bmcl.2025.130502","url":null,"abstract":"<div><div>In this study, five novel SKF-83566 derivatives (8a–8e) were synthesized by covalently linking pomalidomide to SKF-83566, which features a benzazepine skeleton, via flexible linker chains. Their structures were confirmed using ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry. The antiproliferative activity against HeLa (cervical cancer) and MDA-MB-231 (breast cancer) cells was evaluated using the MTT assay, with SKF-83566, pomalidomide, and 5-fluorouracil (5-FU) serving as controls. The results indicate that most derivatives demonstrated superior activity compared to the control drug, with compound 8a exhibiting the highest potency: an IC₅₀ of 5.50 ± 0.28 μM against MDA-MB-231 cells and 10.13 ± 0.95 μM against HeLa cells. Further experiments demonstrated that 8a inhibits MDA-MB-231 cell colony formation, adhesion, and migration in a concentration-dependent manner, exhibiting a stronger anti-migration effect than 5-Fu. In the MDA-MB-231 cell chicken embryo chorioallantoic membrane (CAM) xenograft model, 8a also showed superior tumor growth inhibition compared to 5-Fu. Structure-activity relationship analysis shows that pomalidomide can enhance the compound's cytotoxicity and targeting ability, while flexible alkyl chains improve cell permeability and target binding capacity. This study confirms that compound 8a has the potential to become a candidate drug for breast cancer treatment, providing a foundation for the development of new antitumor therapies.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130502"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145719949","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 potent and selective RORγ inhibitor for the treatment of autoimmune diseases","authors":"Taku Ikenogami ,&nbsp;Masahiro Yokota ,&nbsp;Shingo Fujioka ,&nbsp;Naoki Ogawa ,&nbsp;Masato Noguchi ,&nbsp;Akihiro Nomura ,&nbsp;Tsuyoshi Adachi ,&nbsp;Yoshiaki Katsuda ,&nbsp;Kojo Arita ,&nbsp;Naoki Miyagawa ,&nbsp;Yusuke Aratsu ,&nbsp;Kota Asahina ,&nbsp;Paul Crowe ,&nbsp;Haiyan Tao ,&nbsp;Scott Thacher ,&nbsp;Makoto Shiozaki","doi":"10.1016/j.bmcl.2025.130494","DOIUrl":"10.1016/j.bmcl.2025.130494","url":null,"abstract":"<div><div>Retinoic acid receptor-related orphan receptor γ (RORγ) is a master transcriptional regulator of Th17 cell differentiation as well as of the production of pro-inflammatory cytokines such as IL-17 and IL-22. Its critical role in Th17 cell function and cytokine production makes it a promising therapeutic target for autoimmune diseases. As a result of our high-throughput screening (HTS) campaign to discover novel chemotypes, we identified Cpd <strong>1</strong>, a dihydropyrimidinone scaffold with desirable drug-like properties, including favorable ligand efficiency (LE) and fraction of sp³ carbons (Fsp³). Initial structure–activity relationship (SAR) exploration led to the identification of Cpd <strong>17</strong>. Target specificity studies of Cpd <strong>17</strong> indicated high selectivity characteristics for the dihydropyrimidinone scaffold. Subsequent X-ray structural analysis revealed its binding mode against RORγ, enabling further optimization by structure-based drug design (SBDD). These efforts culminated in the identification of Cpd <strong>21</strong>, which exhibited significantly improved RORγ inhibitory potency along with LE, and Fsp³ compared to Cpd <strong>1</strong>. These results highlight Cpd <strong>21</strong> as a promising lead compound to explore a novel clinical candidate for the development of RORγ-targeted therapies.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130494"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145719970","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":"Evaluation of the antibacterial activity of diverse coumarin [3,4]-fused tetrahydroheterocycles","authors":"Xiyan Tang,&nbsp;Jie Pang,&nbsp;Yanmin Huang,&nbsp;Jianguo Cui,&nbsp;Chunfang Gan,&nbsp;Zhiping Liu","doi":"10.1016/j.bmcl.2025.130468","DOIUrl":"10.1016/j.bmcl.2025.130468","url":null,"abstract":"<div><div>Three novel classes of coumarin [3,4]-fused tetrahydroheterocyclics were synthesized in one step using donor-acceptor cyclopropane diesters as 1,3-dipoles <em>via</em> a facile [3 + 2]/[3 + 3] annulation/lactonization strategies. The antibacterial activities of these compounds were evaluated against two species of animal-derived pathogenic bacteria (<em>Staphylococcus aureus</em>, <em>Escherichia coli</em>) and three species of plant-derived pathogenic bacteria (<em>Xanthomonas citri</em>, <em>Pseudomonas oryzae</em>, <em>Fusarium oxysporum</em>). The results showed that coumarin-fused tetrahydrofuran compounds (e.g., <strong>3aa</strong>, <strong>3</strong><strong>ac</strong> and <strong>3ae</strong>) exhibited significant selective antibacterial activity against <em>Staphylococcus aureus</em> with a minimum inhibitory concentration (MIC) of 2 μg/mL, while no obvious inhibitory effect was observed against other tested strains. Coumarin-fused tetrahydropyridazines (e.g., <strong>7ad</strong>, <strong>7ae</strong>, <strong>7ah</strong> and <strong>7ag</strong>) displayed excellent antibacterial activity against <em>Pseudomonas oryzae</em> and <em>Fusarium oxysporum</em>, with an MIC value of 2 μg/mL for all, and their antibacterial effect was significantly superior to that of osthol (the positive control). In contrast, coumarin-fused tetrahydro-1,2-oxazines showed relatively weak antibacterial activity, only compounds <strong>5 ac</strong> and <strong>5ak</strong> exerted moderate inhibitory effects on <em>Staphylococcus aureus</em> and <em>Pseudomonas oryzae</em>, both with an MIC value of 4 μg/mL. The findings of this study provide an important theoretical basis for the design and synthesis of novel coumarin-fused tetrahydroheterocyclic antibacterial agents.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130468"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145494233","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 self-assembling peptide platform enables plasma membrane protein degradation","authors":"Wenjie Zhou ,&nbsp;Yanyan Li ,&nbsp;Wenli Shi ,&nbsp;Binghua Cheng ,&nbsp;Jiaming Liang ,&nbsp;Zeyu Zhou ,&nbsp;Hui Tian ,&nbsp;Ximing Shao ,&nbsp;Hongchang Li ,&nbsp;Lijing Fang ,&nbsp;Ke Liu","doi":"10.1016/j.bmcl.2025.130504","DOIUrl":"10.1016/j.bmcl.2025.130504","url":null,"abstract":"<div><div>Plasma membrane proteins at cell surface are critical for numerous physiological and pathological processes and are primary targets for clinical drugs. Given that clustering of plasma membrane proteins by endogenous stimuli or pharmaceutical interventions serves as a key trigger for their internalization and degradation, this process critically influences their function and turnover. Inspired by this natural process, we developed a modular, protein-of-interest (POI) targeting degradation strategy by using a bifunctional chimera molecule composed of a POI-binding ligand and a self-assembling peptide (WIII/YIII). We term this strategy SAILTAC (Self-Assembling Peptide Induced Lysosomal Targeting Chimera) and demonstrate that these chimeras could efficiently degrade membrane-anchored GFP and the therapeutically relevant immune checkpoint PD-L1. An optimized dimeric chimera (YIII-BMS)₂ potently reduced PD-L1 across multiple cancer cell lines through the lysosomal pathway. Collectively, the SAILTAC strategy offers a versatile and targeted approach to degrade plasma membrane proteins, providing a new tool for nanomedicine application.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"132 ","pages":"Article 130504"},"PeriodicalIF":2.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145719910","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}