Bioorganic & Medicinal Chemistry最新文献

{"title":"Thiazolidinones and related analogues as efficient antitrypanosomal agents","authors":"Michal Kolařík ,&nbsp;Kayhan Ilbeigi ,&nbsp;Guy Caljon ,&nbsp;Lucie Brulíková","doi":"10.1016/j.bmc.2025.118363","DOIUrl":"10.1016/j.bmc.2025.118363","url":null,"abstract":"<div><div>We designed and synthesised a series of thiazolidinediones and related analogues and evaluated their antiparasitic activity. A structure-activity relationship (SAR) study focused on modifications of specific parts of the molecule revealed derivatives that displayed significant activity against <em>Trypanosoma brucei</em> species. Notably, the analogue <strong>6i</strong> exhibited exceptional activity, with an EC₅₀ value of 30 nM and a selectivity index of &gt;2000, against the protozoan <em>Trypanosoma brucei rhodesiense</em>, which causes human African trypanosomiasis. Additionally, compounds <strong>6a</strong>, <strong>6k</strong>, <strong>7e</strong>, and <strong>18</strong> demonstrated antitrypanosomal activities in the less than 5 μM range. Our most active analogue <strong>6i</strong> represents a promising candidate for further preclinical development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118363"},"PeriodicalIF":3.0,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144917634","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":"Employing a drug repurposing strategy to identify B-cell lymphoma-2 (BCL-2) inhibitors with anticancer potential: An in silico and in vitro based study","authors":"Ali M. Alaseem ,&nbsp;Glowi Alasiri ,&nbsp;M. Arockia Babu ,&nbsp;Thakur Gurjeet Singh ,&nbsp;Prawez Alam ,&nbsp;Mohammad Fareed ,&nbsp;Mohammad Suhail Akhter ,&nbsp;Nisha Bansal","doi":"10.1016/j.bmc.2025.118364","DOIUrl":"10.1016/j.bmc.2025.118364","url":null,"abstract":"<div><div>BCL-2 (B-cell lymphoma-2) is a key protein overexpressed in numerous cancers. Further, its association with cancer cell survival, prognosis, and ability to evade apoptosis makes it an important drug target in cancer chemotherapy. Venetoclax (ABP199) is the only FDA-approved BCL-2 inhibitor for chronic lymphocytic leukemia (CLL). Nevertheless, the BCL-2 active domain mutations, toxicity, and chemoresistance associated with ABP199 further dampen its future efficacy and positive outcome. Considering the gap and quest for rapid drug discovery, we applied the drug repurposing utility on the database of 3584 drugs (HY-L066, from MedChemExpress (MCE)) from sources like USFDA, EMA, NMPA, PMDA, and Pharmacopeia to identify a plausible lead with the potency to inhibit BCL-2. The HTVS, followed by molecular docking, mechanics using prime MMGB-SA free energy calculations, and MD simulation, led us to identify Stevioside A as a structural lead for the BCL-2. Stevioside displayed a profound and robust interaction and the binding pose within the receptor catalytic site via hydrogen bonding with the ASP103 (hydroxyl group), GLN99 (via the oxygen atoms), and TYR202. TYR202 was also associated with the π-π stacking with the aromatic ring of stevioside, further stabilizing its orientation and affinity towards the receptor. Furthermore, in western blotting studies, the maximal impact of Stevioside was observed at 750 nM concentration, whereby it halved the BCL-2 expression in comparison to the untreated control. This response was comparable to the venetoclax. The outcome hence presents a scope to explore Stevioside A and other top hits in the biological arena and establish their impact as BCL-2 antagonists.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118364"},"PeriodicalIF":3.0,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144890953","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":"Self-assembled dual-target ibuprofen-irinotecan conjugate for colorectal cancer therapy","authors":"Lumei Dai ,&nbsp;Shifang Wen ,&nbsp;Yaling Chen ,&nbsp;Xinchun Li ,&nbsp;Bing Zhao ,&nbsp;Xinyu You ,&nbsp;Rongqiang Li ,&nbsp;Bin Zhang","doi":"10.1016/j.bmc.2025.118367","DOIUrl":"10.1016/j.bmc.2025.118367","url":null,"abstract":"<div><div>Self-assembled nanodrug conjugates utilize both hydrophilic and hydrophobic ligands for targeted tumor delivery, reducing systemic toxicity while enhancing therapeutic efficacy. Herein, four novel nonsteroidal anti-inflammatory drug (NSAID)-irinotecan (Ir) conjugates were synthesized by forming ester bonds between hydrophobic NSAIDs and hydrophilic Ir. These amphiphilic conjugates self-assembled into carrier-free NSAID-Ir nanoparticles (NPs) in aqueous solution. Among them, Ibu-Ir NPs demonstrated superior activity against HT-29 cells (IC₅₀ = 1.15 μM), showing 5.6-fold greater potency than free Ir. Mechanistically, Ibu-Ir NPs downregulated cyclooxygenase-2 and topoisomerase I expression, enhancing Ir's therapeutic effect. In HT-29 xenograft models, Ibu-Ir NPs was able to inhibit tumor growth, although the small sample size (<em>n</em> = 3) carries a high risk of statistical errors. This simple yet potent strategy combines anti-inflammatory and anticancer actions, demonstrating significant potential for colorectal cancer therapy.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118367"},"PeriodicalIF":3.0,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144891917","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 bromobenzyl phenyl ether derivative YPD-29B: a novel pre-clinical compound targeting the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) interaction","authors":"Yang Yang ,&nbsp;Meiqin Xu ,&nbsp;Ke Wang ,&nbsp;Liang Xia ,&nbsp;Qianchen Ning ,&nbsp;Xintong Wu ,&nbsp;Xinyue Zang ,&nbsp;Fangfang Lai ,&nbsp;Xiaoguang Chen ,&nbsp;Zhiqiang Feng","doi":"10.1016/j.bmc.2025.118366","DOIUrl":"10.1016/j.bmc.2025.118366","url":null,"abstract":"<div><div>Targeting the PD-1/PD-L1 immune checkpoint pathway with small molecules has exhibited great promise. Herein, to develop the inhibitors with good activity, pharmacokinetic properties and druggability, a novel series of halogens substituted derivatives at the 2-position of the biphenyl group were synthesized, screened, and their inhibitory activity against the PD-1/PD-L1 protein-protein interaction (PPI) was evaluated through a HTRF assay. Among them, <strong>YPD-29B</strong> exhibited potent activity with IC₅₀ value of less than 1 pM. Furthermore, the PBMC-based PD-1/PD-L1 blockade bioassay revealed that <strong>YPD-29B</strong> could inhibit the PD-1/PD-L1 interaction and restore T-cell function with the concentration of 10 nM at the cellular level and with the IC₅₀ value of 0.18 nM. However, the poor solubility of <strong>YPD-29B</strong> limited the evaluation of antitumor activity <em>in vivo</em>. Thus, the prodrug, sodium salt and hydrochloride of <strong>YPD-29B</strong> were designed and synthesized to conduct the animal experiments, revealing the obvious anti-melanoma activity of <strong>YPD-29B-Na</strong> with TGI of 64.11 % and weak toxicity on the blood index and the body weight compared with the positive control CTX. T lymphocyte infiltration markedly increased in tumors of the different treated groups, suggesting the activation of the immune system. Besides, molecular docking verified the rationality of the design. <strong>IMMH-010</strong>, as a prodrug of <strong>YPD-29B</strong> has been approved for clinical phase I by NMPA. We hope these above results could offer a novel perspective for the development of PD-1/PD-L1 small molecule inhibitors.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118366"},"PeriodicalIF":3.0,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144890954","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 and synthesis of new pyridazinone derivatives as selective COX-2 inhibitors: In-vitro and in-vivo evaluation of the anti-inflammatory activity, histopathological studies and molecular modelling","authors":"Rasha A. Hassan ,&nbsp;Eman M. Ahmed ,&nbsp;Sara Y. Ewieda ,&nbsp;Amr M. Abdou ,&nbsp;Shaymaa G. Ibrahim ,&nbsp;Sameh S. Zaghlool ,&nbsp;Marwa S.A. Hassan","doi":"10.1016/j.bmc.2025.118348","DOIUrl":"10.1016/j.bmc.2025.118348","url":null,"abstract":"<div><div>New pyridazinone derivatives <strong>3a</strong>–<strong>d</strong>, <strong>4a</strong>, <strong>4b,</strong> and <strong>5a</strong>–<strong>f</strong> were synthesized and tested for <em>in-vitro</em> inhibition of human COX-1 and COX-2. Compounds <strong>5a</strong> and <strong>5f</strong> showed strong COX-2 inhibition (IC₅₀ = 0.77 and 1.89 μM; SI = 16.70 and 13.38) compared to indomethacin (IC₅₀ = 0.42 μM, SI = 0.50) and celecoxib (IC₅₀ = 0.35 μM, SI = 37.03). In LPS-induced RAW264.7 macrophages, ELISA results showed that compound <strong>5a</strong> reduced TNF-α and IL-6 levels by 87 % and 76 %, outperforming celecoxib (67 % and 81 %), while compound <strong>5f</strong> reduced them by 35 % and 32 %. RT-PCR revealed that compound <strong>5a</strong> suppressed TNF-α and IL-6 mRNA by 82 % and 62 % (<em>vs</em> celecoxib 68 % and 70 %), whereas compound <strong>5f</strong> achieved 27 % and 47 % reductions. Both compounds inhibited LPS-mediated NO by 35.7 % for compound <strong>5a</strong> and 20 % for compound <strong>5f</strong> and ROS production (compound <strong>5a</strong>: 42 %, compound <strong>5f</strong>: 21.3 %). <em>In vivo</em>, rat paw edema inhibition showed that both had strong anti-inflammatory effects, comparable to indomethacin and celecoxib, with a lower ulcer number and index compared to the indomethacin group. Gastric mucosal protection was 99.77 % for compound <strong>5a</strong> and 83.08 % for compound <strong>5f</strong>. Histopathology revealed paw tissue from treated groups had healthy epidermal layers with reduced inflammation. Stomach tissue from compound <strong>5a</strong>-treated rats showed moderate tunica mucosa improvement and epithelial layer degeneration; compound <strong>5f</strong> showed mild fundic mucosa improvement with inflammatory infiltration and mucosal desquamation. In paw tissue, both compounds reduced iNOS protein expression and significantly suppressed NF-κB. Molecular modelling indicated strong COX-2 binding affinities. ADME profiling confirmed drug-likeness: compound <strong>5a</strong> fully complied with Veber's rules; compound <strong>5f</strong> met Lipinski and Egan criteria without violations. Overall, compounds <strong>5a</strong> and <strong>5f</strong> demonstrate potent COX-2 selectivity, anti-inflammatory activity, reduced gastric toxicity, and favorable pharmacokinetics, positioning them as promising leads for safe and effective anti-inflammatory drug development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118348"},"PeriodicalIF":3.0,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144860446","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":"Identification of pyrazole-acrylonitrile derivatives as potential anticancer agents and mechanistic insights","authors":"K. Fabitha ,&nbsp;Munugala Chandrakanth ,&nbsp;Anoop Kallingal ,&nbsp;Natalia Maciejewska ,&nbsp;Praveen Telukuntla ,&nbsp;Ramesh Gondru ,&nbsp;Ranjith Kumavath ,&nbsp;T.D. Demina ,&nbsp;Majed Alharbi ,&nbsp;Janardhan Banothu","doi":"10.1016/j.bmc.2025.118352","DOIUrl":"10.1016/j.bmc.2025.118352","url":null,"abstract":"<div><div>Developing highly effective anticancer drugs remains a primary focus for drug designers worldwide. In this investigation, we designed and developed novel pyrazole-acrylonitriles incorporating various <em>N</em>-heterocyclic groups and evaluated their anticancer properties. Comprehensive <em>in vitro</em> profiling included evaluation of cell cytotoxicity, colony formation and cell adhesion in 3D cultures, cell cycle analysis, DNA damage induction, and apoptosis. Among the synthesized compounds, <strong>8b</strong> and <strong>8c</strong> demonstrated enhanced sensitivity and potency with IC₅₀ values of 2.58 ± 0.053 μM and 2.34 ± 0.074 μM, respectively, against the MCF7 cell line. Furthermore, compounds <strong>8e</strong> and <strong>9c</strong> exhibited IC₅₀ values of 2.09 ± 0.464 μM and 1.65 ± 0.006 μM against A549, while compounds <strong>9b</strong> and <strong>9f</strong> displayed values of 4.84 ± 0.035 μM and 4.89 ± 0.053 μM on the HCT116 cell line. All these compounds exhibited greater potency than the standard drug, cisplatin. Our findings suggest that potent pyrazole derivatives effectively inhibited cell proliferation by inducing cell cycle arrest, promoted significant DNA fragmentation, and demonstrated superior apoptotic activity compared to the standard drug Etoposide. Moreover<em>, In silico</em> studies revealed favorable pharmacokinetic profiles and non-carcinogenicity for all potent compounds. Therefore, the potent pyrazole-acrylonitriles can serve as lead compounds for further <em>in vivo</em> investigations and the design and development of new drug candidates.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118352"},"PeriodicalIF":3.0,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144890952","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":"(±)-Agrimonolide: Efficient synthesis and treatment of inflammatory bowel disease via JAK1/STAT3 pathway inhibition","authors":"Xiao Zhang ,&nbsp;Mingqian Ju ,&nbsp;Nanting Zou ,&nbsp;Tao Liang ,&nbsp;Xiaohong Li ,&nbsp;Chunping Wan ,&nbsp;Zewei Mao","doi":"10.1016/j.bmc.2025.118351","DOIUrl":"10.1016/j.bmc.2025.118351","url":null,"abstract":"<div><div>Inflammatory bowel disease (IBD) is a chronic and relapsing intestinal disorder. Here, we developed an efficient total synthesis of (±)-agrimonolide, a compound derived from the traditional medicine <em>Agrimonia pilosa Ledeb</em>., and evaluated its anti-inflammatory effects in a DSS-induced ulcerative colitis (UC) mouse model. Treatment with (±)-agrimonolide significantly ameliorated colonic inflammation, as evidenced by reducing mucosal damage, decreasing inflammatory cell infiltration, and suppressing the JAK1/STAT3 pathway activation in colonic tissues. These findings strongly suggest that (±)-agrimonolide may serve as a potential therapeutic agent for treating IBD.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118351"},"PeriodicalIF":3.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144865508","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":"Transcript and temporal-specific RNA nucleotide editing technologies","authors":"Rushdhi Rauff ,&nbsp;Chanjuan Dong ,&nbsp;Shiva Ayyar,&nbsp;Fu-Sen Liang","doi":"10.1016/j.bmc.2025.118346","DOIUrl":"10.1016/j.bmc.2025.118346","url":null,"abstract":"<div><div>Modified RNA nucleotides have emerged as a rapidly growing field due to their critical roles in post-transcriptional gene regulation. Early approaches investigating epitranscriptomic regulation primarily involved altering the expression of RNA nucleotide editing enzymes. However, the global perturbation of RNA nucleotide modifications complicates the investigation of site-specific effects of individual modifications on transcripts. To address this limitation, researchers have developed novel RNA modification editing tools that use CRISPR, antisense oligonucleotides (ASOs), chemical ligands, and light to selectively target RNA editing enzymes to chosen RNA sites with precise temporal control. In this review, we provide a comprehensive overview of current spatiotemporal controlled RNA nucleotide editing technologies.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118346"},"PeriodicalIF":3.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144865509","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 1,8-cineole derivatives and evaluation of their cytoprotective effects against cisplatin-induced HK-2 cell injury","authors":"Xinyao Pan ,&nbsp;Xiaodan Wang ,&nbsp;Yun Yang ,&nbsp;Ziwei Le ,&nbsp;Shiyu Wang ,&nbsp;Yao Shen ,&nbsp;Hongbo Dong ,&nbsp;Kaifeng Lai ,&nbsp;Congcong Lin ,&nbsp;Chunjuan Yang ,&nbsp;Huanjun Xu ,&nbsp;Chunli Gan","doi":"10.1016/j.bmc.2025.118347","DOIUrl":"10.1016/j.bmc.2025.118347","url":null,"abstract":"<div><div>This study aimed to discover novel lead compounds for acute kidney injury (AKI) treatment by rationally designing and synthesizing 18 derivatives through structural modifications of 1,8-cineole (c0), a nephroprotective natural product. Initial in vitro screening identified derivative 3c-2 as the most promising candidate. Subsequent evaluations in cisplatin-injured HK-2 cells demonstrated that 3c-2 effectively attenuated cisplatin-induced oxidative stress by reducing reactive oxygen species (ROS) and malondialdehyde (MDA) generation, and enhancing superoxide dismutase (SOD) activity. Comprehensive evaluations combining mitochondrial membrane potential (MMP) measurements and flow cytometry-based apoptosis assays consistently demonstrated that compound 3c-2 possessed a significant inhibitory effect on apoptosis and was effective in attenuating cisplatin-induced cytotoxicity in HK-2 renal tubular epithelial cells. Molecular docking and dynamics simulations indicated stable binding between 3c-2 and PI3K, a key regulator of oxidative stress and apoptosis pathways, suggesting PI3K as the potential therapeutic target of 3c-2.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118347"},"PeriodicalIF":3.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144828451","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":"ClpP-based MtPTAC technology enables targeted degradation of inner mitochondrial membrane proteins","authors":"Yuxin Yao ,&nbsp;Dachi Wang ,&nbsp;Haoyu Gong ,&nbsp;Ruibin Jiang ,&nbsp;Yang Liu ,&nbsp;Yijun Liu ,&nbsp;Xin Lai ,&nbsp;Zhaoyang Xu ,&nbsp;Wei Zhou ,&nbsp;Haorong Li ,&nbsp;Xiaohong Fang","doi":"10.1016/j.bmc.2025.118350","DOIUrl":"10.1016/j.bmc.2025.118350","url":null,"abstract":"<div><div>Mitochondrial proteostasis is essential for tumorigenesis, and mitochondrial inner membrane proteins have emerged as meaningful targets due to their crucial functions in regulating apoptosis, maintaining oxidative phosphorylation, and influencing tumor initiation and progression. Targeted protein degradation (TPD) has garnered significant attention as a promising therapeutic approach. However, conventional TPD platforms relying on the ubiquitin-proteasome system or lysosomal pathways encounter inherent obstacles in targeting proteins sequestered within the mitochondrial compartment and cannot degrade mitochondrial inner membrane proteins. Utilizing our previously established MtPTAC system, we selected dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme in de novo pyrimidine biosynthesis, as a model substrate. We designed and synthesized a series of degraders, with 3D-2 achieving over 50 % degradation efficiency of DHODH via the ClpP protease. This degrader can form a stable ternary complex with DHODH and ClpP, and it exhibits significant inhibitory effects across various tumor cell lines. This technological innovation is the first to successfully degrade endogenous mitochondrial inner membrane proteins. It provides a diverse toolkit for investigating mitochondrial protein functions and paving the way for novel anticancer therapies</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"130 ","pages":"Article 118350"},"PeriodicalIF":3.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144865505","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}