{"title":"Self-Assembling Amphiphilic Peptides Target the VDAC1-Hexokinase-II Complex to Induce Apoptosis in Cervical Carcinoma Cells","authors":"Wanfeng Sun, , , Angelina Angelova, , , Xintong Han, , , Xibai Wang, , , Borislav Angelov, , , Qibin Chen, , , Na Li*, , and , Aihua Zou*, ","doi":"10.1021/acs.jmedchem.4c02789","DOIUrl":"10.1021/acs.jmedchem.4c02789","url":null,"abstract":"<p >VDAC1, an outer mitochondrial membrane protein overexpressed in cancers, regulates apoptosis by interacting with antiapoptotic proteins and releasing apoptotic factors. We investigate novel multiblock cationic peptide amphiphiles targeting the VDAC1-Hexokinase-II complex in the mitochondria of cervical carcinoma cells. Amphiphilic peptide variants were designed by modifying the C-terminus of VDAC1 fragment LP1 with a cationic hydrophilic segment and the N-terminus with a hydrophobic domain, enabling self-assembly into nanofiber-like structures at elevated concentrations. In HeLa cells, these peptides triggered mitochondrial-mediated apoptosis through a decrease of the mitochondrial membrane potential, cytochrome <i>C</i> release, and caspase activation, suggesting a disrupted VDAC1–HK-II interaction. The mitochondria-targeting peptides showed notable selective cytotoxicity to cancer cells, with minimal effects on normal 3T3 cells. Our findings demonstrate that amphiphilic peptides for VDAC1-HK-II-targeting represent a promising mitochondria-focused therapeutic strategy for cervical cancer inhibition, combining structural self-assembly properties with enhanced apoptotic efficacy in malignant cells.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 18","pages":"18857–18868"},"PeriodicalIF":6.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145043536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jiwoong Lim, , , Lilly F. Chiou, , , Brandon Novy, , , Emma J. Chow, , , Jacqueline L. Norris-Drouin, , , P. Brian Hardy, , , Konstantin I. Popov, , , Cyrus Vaziri, , , Albert A. Bowers*, , and , Kenneth H. Pearce*,
{"title":"Development of Next Generation Cell-Permeable Peptide Inhibitors for the Oncological Target MAGE-A4","authors":"Jiwoong Lim, , , Lilly F. Chiou, , , Brandon Novy, , , Emma J. Chow, , , Jacqueline L. Norris-Drouin, , , P. Brian Hardy, , , Konstantin I. Popov, , , Cyrus Vaziri, , , Albert A. Bowers*, , and , Kenneth H. Pearce*, ","doi":"10.1021/acs.jmedchem.5c01540","DOIUrl":"10.1021/acs.jmedchem.5c01540","url":null,"abstract":"<p >Melanoma-associated antigen A4 (MAGE-A4) is a cancer/testis antigen (CTA) that interacts with the E3 ubiquitin ligase RAD18 to enhance DNA damage tolerance in tumor cells. Here, we report the structure-guided optimization of a previously reported potent but cell-impermeable cyclic peptide, called <b>MTP-1</b>. Building off our previous peptide inhibitor efforts, we aimed to develop next-generation peptide inhibitors with significantly improved cell permeability. Through systematic structure–activity relationship (SAR) studies employing an mRNA display site-saturation mutagenesis library (SSML) and strategic scaffold optimization with modified cyclization strategy, we developed <b>JWP24</b>, the first cell-permeable peptide inhibitor of MAGE-A4. Evaluation across multiple assays demonstrates intracellular target engagement, maintained binding potency, and exhibits no cytotoxicity at effective concentrations. This study provides a valuable framework for transforming potent but larger, macrocyclic peptide inhibitors into cell-permeable probes. The work presented here demonstrates progress toward further establishing MAGE-A4 as a chemically tractable oncology target.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 18","pages":"19377–19395"},"PeriodicalIF":6.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Venkatesh Sarampally,Soumyadeep Poddar,Pragya Trivedi,Abhilash Rana,Ajay K Singh,Kunta Chandra Shekar,Biswajit Saha,Avijit Jana
{"title":"\"NO\" Means Yes: Unlocking the Therapeutic Synergy of Nitric Oxide (NO) and Chlorambucil (Cbl) via Photoresponsive Sequential Delivery in a Triple-Negative Breast Cancer 3D Spheroidal Platform with Transcriptomic Insights.","authors":"Venkatesh Sarampally,Soumyadeep Poddar,Pragya Trivedi,Abhilash Rana,Ajay K Singh,Kunta Chandra Shekar,Biswajit Saha,Avijit Jana","doi":"10.1021/acs.jmedchem.5c01995","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01995","url":null,"abstract":"Nitric oxide (NO) is a multifunctional signaling molecule in oncology, influencing tumor progression, apoptosis, and immune responses. In contrast, chlorambucil (Cbl), a DNA-alkylating chemotherapeutic, induces cytotoxicity through DNA damage. Here, we report a photoresponsive nanoparticle platform for sequential codelivery of NO and Cbl, where NO is released within 10 min of irradiation, followed by Cbl release within 30 min. The nanoplatform employs a coumarin-4-ylmethyl photoremovable protecting group (PRPG) to achieve light-triggered spatiotemporal release of both agents. Using 2D cultures and 3D triple-negative breast cancer (TNBC) spheroids, we observed that NO-assisted chemotherapy markedly improved tumor inhibition and apoptosis compared to Cbl alone. Transcriptomic profiling (RNA-seq) revealed modulation of oncogenic pathways (PI3K/AKT, NF-κB, MAPK, EMT) with upregulation of tumor suppressors (TP53, CASP10, TIMP1) and downregulation of oncogenes (BCL2, MMP9, VEGFC). Additionally, suppression of IL-6, TNF-α, and ECM remodeling factors indicated reduced metastatic potential. This strategy highlights NO-mediated synergy as a promising approach to overcome chemoresistance in TNBC.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"45 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Philipp Flury, , , Jyoti Vishwakarma, , , Katharina Sylvester, , , Nobuyo Higashi-Kuwata, , , Agnieszka K. Dabrowska, , , Renee Delgado, , , Ashley Cuell, , , Rahul Basu, , , Alexander B. Taylor, , , Ellen Gonçalves de Oliveira, , , Mateus Sá Magalhães Serafim, , , Jingxin Qiao, , , Yan Chen, , , Shengyong Yang, , , Anthony J. O’Donoghue, , , Hiroaki Mitsuya, , , Michael Gütschow, , , Stefan A. Laufer, , , Christa E. Müller, , , Reuben S. Harris, , and , Thanigaimalai Pillaiyar*,
{"title":"Azapeptide-Based SARS-CoV-2 Main Protease Inhibitors: Design, Synthesis, Enzyme Inhibition, Structural Determination, and Antiviral Activity","authors":"Philipp Flury, , , Jyoti Vishwakarma, , , Katharina Sylvester, , , Nobuyo Higashi-Kuwata, , , Agnieszka K. Dabrowska, , , Renee Delgado, , , Ashley Cuell, , , Rahul Basu, , , Alexander B. Taylor, , , Ellen Gonçalves de Oliveira, , , Mateus Sá Magalhães Serafim, , , Jingxin Qiao, , , Yan Chen, , , Shengyong Yang, , , Anthony J. O’Donoghue, , , Hiroaki Mitsuya, , , Michael Gütschow, , , Stefan A. Laufer, , , Christa E. Müller, , , Reuben S. Harris, , and , Thanigaimalai Pillaiyar*, ","doi":"10.1021/acs.jmedchem.5c01520","DOIUrl":"10.1021/acs.jmedchem.5c01520","url":null,"abstract":"<p >M<sup>pro</sup> of SARS-CoV-2 plays a vital role in the replication and pathogenesis of virus. Additionally, its high conservation within the <i>Coronaviridae</i> family makes it an attractive therapeutic target for developing broad-spectrum agents. This study describes the design, synthesis, and structure−activity relationships of azapeptide-based SARS-CoV-2 M<sup>pro</sup> inhibitors, leading to several compounds with nanomolar IC<sub>50</sub> values. Examples include <b>14r</b> (IC<sub>50</sub> = 13.3 nM), <b>14s</b> (IC<sub>50</sub> = 30.6 nM), <b>20a</b> (<b>TPG-20a</b>, IC<sub>50</sub> = 28.0 nM), and <b>20g</b> (IC<sub>50</sub> = 30.4 nM). Some compounds inhibit MERS-CoV and SARS-CoV-1 M<sup>pro</sup> but not the human protease cathepsin L. Several inhibitors, such as <b>20a</b> and <b>20f</b>, exhibit antiviral activity with potencies comparable to nirmatrelvir and activity against the E166V-carrying SARS-CoV-2 variant (SARS-CoV-2<sup>E166V</sup>). An M<sup>pro</sup> cocrystal structure with <b>20a</b> shows a covalent adduct with the catalytic Cys145. Overall, these new inhibitors are promising chemical tools that may contribute to the identification of future pan-anticoronaviral drugs.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 18","pages":"19339–19376"},"PeriodicalIF":6.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.5c01520","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vijay Babu Pathi, , , Sunny Kumar, , , Asikul Sk, , , Subhankar Shee, , , Mrinal K. Ghosh*, , and , Biswadip Banerji*,
{"title":"Isoquinolinone–Naphthoquinone Hybrids as Potent PARP-1 Inhibitors Induce Apoptosis in Glioma via DNA Damage and ROS Generation","authors":"Vijay Babu Pathi, , , Sunny Kumar, , , Asikul Sk, , , Subhankar Shee, , , Mrinal K. Ghosh*, , and , Biswadip Banerji*, ","doi":"10.1021/acs.jmedchem.5c01229","DOIUrl":"10.1021/acs.jmedchem.5c01229","url":null,"abstract":"<p >We report a series of fused isoquinolinone–naphthoquinone hybrid molecules as PARP-1 inhibitors. Our efforts led to the identification of compounds <b>5c</b> and <b>5d</b>, which display potent PARP-1 inhibition in enzymatic assays with IC<sub>50</sub> values of 2.4 and 4.8 nM and demonstrated consistent antiproliferative activity in C6 glioma cells, with IC<sub>5</sub><sub>0</sub> values of 1.34 ± 0.02 and 1.35 ± 0.009 μM, respectively. Notably, both molecules showed similar efficacy in U87MG glioma cells with IC<sub>5</sub><sub>0</sub> values of 1.28 ± 0.03 and 1.33 ± 0.01 μM, respectively. <b>5c</b> and <b>5d</b> induced apoptosis in both glioma cells by promoting PARP cleavage, triggering DNA damage, and increasing ROS. Furthermore, they effectively inhibited cell migration and significantly reduced colony formation in both glioma cells. Thus, the results identify the hybrid isoquinolinone–naphthoquinone scaffolds (<b>5c</b> and <b>5d</b>) as a promising lead hit for PARP-1 inhibition in glioma, offering a new scaffold for future drug development.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 18","pages":"19153–19168"},"PeriodicalIF":6.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dazhou Shi, Mei Wang, Craig W. Lindsley*, Shujing Xu*, Yundong Sun* and Peng Zhan*,
{"title":"Anti-infective Drug Discovery: Harnessing Multimechanistic Molecules and Emergent Properties to Defeat Pathogenic Complexity","authors":"Dazhou Shi, Mei Wang, Craig W. Lindsley*, Shujing Xu*, Yundong Sun* and Peng Zhan*, ","doi":"10.1021/acs.jmedchem.5c02312","DOIUrl":"10.1021/acs.jmedchem.5c02312","url":null,"abstract":"","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 17","pages":"18017–18023"},"PeriodicalIF":6.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yi Yang, , , Jiafei Wu, , , Gongyun He, , , Siqi Yao, , , Li-Yuan Wei, , , Quan Wang, , , Wei Dai, , , Han Yuan, , , Jianwen Chen*, , , Xiaoying Wang*, , and , Lei Guo*,
{"title":"Discovery of a Novel COS/H2S-Donor Hybridized sGC Stimulator for Alleviating Isoproterenol-Induced Myocardial Fibrosis","authors":"Yi Yang, , , Jiafei Wu, , , Gongyun He, , , Siqi Yao, , , Li-Yuan Wei, , , Quan Wang, , , Wei Dai, , , Han Yuan, , , Jianwen Chen*, , , Xiaoying Wang*, , and , Lei Guo*, ","doi":"10.1021/acs.jmedchem.5c02191","DOIUrl":"10.1021/acs.jmedchem.5c02191","url":null,"abstract":"<p >Myocardial fibrosis contributes to heart failure (HF) progression, which is associated with impaired nitric oxide (NO)–soluble guanylyl cyclase (sGC)–cyclic guanosine monophosphate (cGMP) signaling. Hydrogen sulfide (H<sub>2</sub>S), a cardioprotective gasotransmitter, is reduced in patients with HF. Therapeutic options targeting both sGC activation and H<sub>2</sub>S enhancement remain limited. We have developed a novel carbonyl sulfide (COS)/H<sub>2</sub>S-donor hybrid sGC stimulator, <b>COS-A</b>, which exhibits a well-characterized H<sub>2</sub>S-releasing property. Compound <b>COS-A</b> outperformed vericiguat in sGC activation in vitro and reduced fibrosis in transforming growth factor-beta 1 (TGF-β1)-treated cardiac fibroblasts by increasing cGMP and H<sub>2</sub>S levels. In isoproterenol (ISO)-induced HF mice, <b>COS-A</b> improved cardiac function comparably to vericiguat. Histological findings revealed its antifibrotic effects through sGC activation and elevation of H<sub>2</sub>S. Our findings indicate that this COS/H<sub>2</sub>S-donor hybridized sGC stimulator holds therapeutic promise for HF treatment.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 18","pages":"19781–19790"},"PeriodicalIF":6.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Discovery of Tricyclic Derivative as Novel and Potent Respiratory Syncytial Virus Fusion Glycoprotein Inhibitor with an Improved Pharmacokinetic Profile","authors":"Li’ao Zhang, , , Bao Xue, , , Mingkang Cao, , , Yuhan Mao, , , Feihai Ma, , , Limei Wang, , , Xiaolei Yang, , , Xinyi Zhao, , , Zhixia Qiu, , , Jielin Tang, , , Min Guo, , , Jinlei Bian, , , Xinwen Chen*, , , Zhiyu Li*, , , Xi Xu*, , and , Qi Yang*, ","doi":"10.1021/acs.jmedchem.5c00692","DOIUrl":"10.1021/acs.jmedchem.5c00692","url":null,"abstract":"<p >Respiratory syncytial virus (RSV) is a major pathogen causing acute respiratory infections, and the RSV fusion glycoprotein (F) has been identified as a key target for developing small-molecule inhibitors. Based on our prior identification of lonafarnib as an F protein inhibitor, medicinal chemistry efforts led to the development of <b>CGR-51</b>, which exhibits significantly enhanced potency against both laboratory and clinical RSV isolates in cellular assays. Time-of-addition and SPR assays indicate that <b>CGR-51</b> inhibits viral entry by targeting the RSV F protein, but has farnesyltransferase-independent antiviral efficacy. Passage of RSV with <b>CGR-51</b> selects for phenotypic resistance with the emergence of the K399N mutation in the RSV F protein. Additionally, <b>CGR-51</b> exhibits an improved pharmacokinetic profile and effectively suppresses RSV replication in a BALB/c mouse model of RSV infection, while showing lower toxicity compared to lonafarnib. Collectively, <b>CGR-51</b> represents a promising RSV F protein inhibitor candidate for the treatment of RSV infection.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 18","pages":"18949–18987"},"PeriodicalIF":6.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"NIR-II Light-Controlled Photosynthetic Activation via an Upconversion Nanoplatform for Targeted Bioenergetic Therapy in Acute Kidney Injury","authors":"Xiaojuan Hu, , , Xingwen Cheng, , , Liqiang Shao, , , Lan Yang, , , Gongning Chen, , , Zhangwei Yan, , , Mengdie Yu, , , Yehui Kang, , , Xiaozhou Mou*, , , Xianghong Yang*, , and , Yu Cai*, ","doi":"10.1021/acs.jmedchem.5c02109","DOIUrl":"10.1021/acs.jmedchem.5c02109","url":null,"abstract":"<p >Acute kidney injury (AKI) causes renal tubular damage, driven primarily by mitochondrial dysfunction and reactive oxygen species (ROS)-mediated oxidative stress, leading to a cellular energy crisis. The physiological architecture of the kidney hampers targeted drug delivery, rendering metabolic restoration a therapeutic challenge. To address this, we developed a second near-infrared (NIR-II) light-driven, bioenergetic nanoplatform (UCTR) that leverages upconversion nanoparticle (UCNPs)-enhanced photosynthesis for energy replenishment and mitochondrial repair in AKI. The UCTR consists of thylakoid membrane (TM)-encapsulated UCNPs cloaked with activated renal tubular epithelial cell membranes (RECM), enabling targeted accumulation in injured tubules. The UCNPs convert deep-tissue-penetrating NIR-II light into visible wavelengths, activating photosynthetic adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide phosphate (NADPH) synthesis within the TM component under irradiation. This exogenous bioenergetic supply mitigates hypoxia-induced mitochondrial energy deficits, while the AMPK/PGC-1α pathway is simultaneously activated to restore the mitochondrial membrane potential. Moreover, UCTR synergizes the antioxidative and anti-inflammatory effects of plantain, accelerating tubular repair.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 18","pages":"19746–19766"},"PeriodicalIF":6.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jinbiao Liao, , , Jianing Liao, , , Yanzhen Yu, , , Kaixin Le, , , Wei Hou, , , Lvtao Cai, , , Geng Chen, , , Tingjun Hou, , , Dan Li*, , and , Rong Sheng*,
{"title":"Discovery of N-(thiazol-2-yl) Furanamide Derivatives as Potent Orally Efficacious AR Antagonists with Low BBB Permeability","authors":"Jinbiao Liao, , , Jianing Liao, , , Yanzhen Yu, , , Kaixin Le, , , Wei Hou, , , Lvtao Cai, , , Geng Chen, , , Tingjun Hou, , , Dan Li*, , and , Rong Sheng*, ","doi":"10.1021/acs.jmedchem.5c02089","DOIUrl":"10.1021/acs.jmedchem.5c02089","url":null,"abstract":"<p >Resistance-conferring mutations in the androgen receptor (AR) ligand-binding pocket (LBP) compromise the effectiveness of clinically approved orthosteric AR antagonists. Targeting the dimerization interface pocket (DIP) of AR presents a promising therapeutic approach. In this study, we report the design and optimization of <i>N</i>-(thiazol-2-yl) furanamide derivatives as novel AR DIP antagonists, among which <b>C13</b> was the most promising candidate. <b>C13</b> exhibited excellent AR antagonistic activity (IC<sub>50</sub> = 0.010 μM), effectively blocked AR dimerization and nuclear translocation, and demonstrated potent efficacy in several castration-resistant prostate cancer (CRPC) cells. Notably, <b>C13</b> showed superior efficacy against variant drug-resistant AR mutants, along with favorable metabolic stability, excellent pharmacokinetic properties, and low brain distribution. Furthermore, oral administration of <b>C13</b> achieved 123.4% tumor growth inhibition in an LNCaP xenograft model without apparent toxicity. As a noncompetitive binder, <b>C13</b> complements current LBP-targeting AR inhibitors and represents a promising therapy for drug-resistant PCa.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 18","pages":"19688–19713"},"PeriodicalIF":6.8,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145026090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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