Hepatocellular carcinoma (HCC) poses significant clinical challenges, including high recurrence, mortality, and drug resistance, underscoring the urgent needs for novel targeted therapies. Lin28B, an RNA-binding protein frequently overexpressed in HCC, promotes tumor progression by enhancing oncogenic signaling pathways and inhibiting the maturation of tumor-suppressive let-7 family miRNAs. However, due to the lack of conventional small-molecule binding pockets, Lin28B has long been considered an undruggable target. In this study, a series of pre-let-7-PROTACs were constructed by conjugating pre-let-7 family miRNAs and E3 ligase ligands. Most pre-let-7-PROTACs achieved efficient and specific degradation of Lin28B and restored endogenous mature let-7 expression, thereby suppressing HCC cell proliferation and migration, promoting apoptosis, and enhancing chemosensitivity. In a Huh-7 xenograft tumor model, pre-let-7-PROTACs exhibited significant synergistic antitumor effects when combined with sorafenib (SFB). This study confirmed that pre-let-7-PROTACs reduce tumor stemness by degrading Lin28B, offering a promising therapeutic approach for HCC.
{"title":"Targeted Degradation of Lin28B Using Pre-let-7-PROTACs for Hepatocellular Carcinoma Therapy.","authors":"Jianfei Xu, Xingxing Liang, Zhaopeng Yan, Yuejie Zhu, Jing Wang, Qian Wang, Zhenjun Yang, Xinjing Tang","doi":"10.1021/acs.jmedchem.5c03203","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03203","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) poses significant clinical challenges, including high recurrence, mortality, and drug resistance, underscoring the urgent needs for novel targeted therapies. Lin28B, an RNA-binding protein frequently overexpressed in HCC, promotes tumor progression by enhancing oncogenic signaling pathways and inhibiting the maturation of tumor-suppressive let-7 family miRNAs. However, due to the lack of conventional small-molecule binding pockets, Lin28B has long been considered an undruggable target. In this study, a series of pre-let-7-PROTACs were constructed by conjugating pre-let-7 family miRNAs and E3 ligase ligands. Most pre-let-7-PROTACs achieved efficient and specific degradation of Lin28B and restored endogenous mature let-7 expression, thereby suppressing HCC cell proliferation and migration, promoting apoptosis, and enhancing chemosensitivity. In a Huh-7 xenograft tumor model, pre-let-7-PROTACs exhibited significant synergistic antitumor effects when combined with sorafenib (SFB). This study confirmed that pre-let-7-PROTACs reduce tumor stemness by degrading Lin28B, offering a promising therapeutic approach for HCC.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146130524","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}
CBP/p300 and BRD4 synergistically drive prostate cancer progression. Here, we report the rational design, synthesis, and biological evaluation of novel PROTACs capable of simultaneously degrading CBP/p300 and BRD4. The representative compounds 10h and 29c induced robust degradation of both targets with DC50 values ranging from 8.8 pM to 10.5 nM in PC-3 prostate cancer cells, accompanied by marked downregulation of c-Myc and acetylated H3K27. Both compounds displayed potent antiproliferative activity across multiple cancer cell lines, with higher potency than NEO2734, paclitaxel (PTX), and ARV-771. In a PC-3 xenograft mouse model, compound 29c achieved dose-dependent tumor growth inhibition (TGI) of up to 81.5% at a low dose of 0.2 mg/kg, administered every other day, significantly surpassing the efficacy of NEO2734 and PTX at higher doses. Together, 29c, a highly efficient CBP/p300 and BRD4 dual-target degrader, demonstrates significant therapeutic potential in prostate cancer and warrants further development.
{"title":"Discovery of Novel CBP/p300 and BRD4 Dual-Target PROTACs with Potent Antitumor Activity in Prostate Cancer.","authors":"Yi-Zhe Zhang, Hui-Juan Zhu, Xiao-Xiao Zhou, Shi-Jie Li, Di Han, Feng-Xiang Liu, Hui-Min Zhou, Xin-Yu Jiang, Yuan-Yuan Guan, Hui-Ru Ren, Ying Wang, Wen-Jing Dai, Yi-Bo Ban, Nan Su, Yong-Cheng Ma, Yong-Tao Xu, Sai-Qi Wang, Ying-Chao Duan","doi":"10.1021/acs.jmedchem.5c03168","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03168","url":null,"abstract":"<p><p>CBP/p300 and BRD4 synergistically drive prostate cancer progression. Here, we report the rational design, synthesis, and biological evaluation of novel PROTACs capable of simultaneously degrading CBP/p300 and BRD4. The representative compounds <b>10h</b> and <b>29c</b> induced robust degradation of both targets with DC<sub>50</sub> values ranging from 8.8 pM to 10.5 nM in PC-3 prostate cancer cells, accompanied by marked downregulation of c-Myc and acetylated H3K27. Both compounds displayed potent antiproliferative activity across multiple cancer cell lines, with higher potency than NEO2734, paclitaxel (PTX), and ARV-771. In a PC-3 xenograft mouse model, compound <b>29c</b> achieved dose-dependent tumor growth inhibition (TGI) of up to 81.5% at a low dose of 0.2 mg/kg, administered every other day, significantly surpassing the efficacy of NEO2734 and PTX at higher doses. Together, <b>29c</b>, a highly efficient CBP/p300 and BRD4 dual-target degrader, demonstrates significant therapeutic potential in prostate cancer and warrants further development.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146130529","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}
Pub Date : 2026-02-06DOI: 10.1021/acs.jmedchem.5c02607
Eduardo J. Martinez, Darren H. Wong, Amish J. Patel, Roy J. Vaz, Robert W. Busby, Robert Zahler, Daniel Schefer, Hui Zhao, Xiaoming Xu, Zizhao Liu, Ruifang Meng, Bernd Kaiser, Jianchao Liu, Lei Wen, Rui Liu, Katya Leites, Helen S. Tian, Sohail F. Tavazoie, Masoud F. Tavazoie, Isabel Kurth
Creatine, a naturally occurring guanidine carboxylic acid, serves as a critical energy metabolite in tissues with high energy demands. Certain cancers upregulate creatine metabolism to supplement their energy needs. Ompenaclid, a salt form of the well-studied creatine transporter inhibitor 3-guanidinopropionic acid (β-GPA), is in clinical development for the treatment of patients with colorectal tumors. Existing SLC6A8 inhibitors are low-potency molecules and frequently interact with related transporters. Herein, we report the discovery of SLC6A8 inhibitors with increased selectivity as well as in vitro and in vivo potency. A bioisostere approach was used by replacing the carboxylic acid of β-GPA with surrogate functional groups to achieve these improvements. Docking of these inhibitors into the recently published SLC6A8 cryo-EM structure reveals key binding contacts and supports the observed structure–activity relationships.
{"title":"Carboxylic Acid Bioisosteres of Creatine as Novel and Selective Substrate Competitive Inhibitors of the Creatine Transporter SLC6A8","authors":"Eduardo J. Martinez, Darren H. Wong, Amish J. Patel, Roy J. Vaz, Robert W. Busby, Robert Zahler, Daniel Schefer, Hui Zhao, Xiaoming Xu, Zizhao Liu, Ruifang Meng, Bernd Kaiser, Jianchao Liu, Lei Wen, Rui Liu, Katya Leites, Helen S. Tian, Sohail F. Tavazoie, Masoud F. Tavazoie, Isabel Kurth","doi":"10.1021/acs.jmedchem.5c02607","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02607","url":null,"abstract":"Creatine, a naturally occurring guanidine carboxylic acid, serves as a critical energy metabolite in tissues with high energy demands. Certain cancers upregulate creatine metabolism to supplement their energy needs. Ompenaclid, a salt form of the well-studied creatine transporter inhibitor 3-guanidinopropionic acid (β-GPA), is in clinical development for the treatment of patients with colorectal tumors. Existing SLC6A8 inhibitors are low-potency molecules and frequently interact with related transporters. Herein, we report the discovery of SLC6A8 inhibitors with increased selectivity as well as <i>in vitro</i> and <i>in vivo</i> potency. A bioisostere approach was used by replacing the carboxylic acid of β-GPA with surrogate functional groups to achieve these improvements. Docking of these inhibitors into the recently published SLC6A8 cryo-EM structure reveals key binding contacts and supports the observed structure–activity relationships.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"12 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122289","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}
Pub Date : 2026-02-06DOI: 10.1021/acs.jmedchem.5c03090
Magdalena Kozlikova, Mary Angelia Alfred, Miloslav Machacek, Fabienne Dumoulin, Andrés de la Escosura, Tomasz Goslinski, Marie Halaskova, Jian-Dong Huang, Mei-Rong Ke, Saad Makhseed, Dariusz T. Mlynarczyk, Dennis K. P. Ng, Tomás Torres, Roy C. H. Wong, Petr Zimcik, Veronika Novakova
Phthalocyanines (Pcs) are promising photosensitizers (PSs) for photodynamic therapy (PDT). However, the variability in experimental conditions in in vitro experiments among reported derivatives complicates clear comparisons. In this study, we systematically evaluated a diverse set of more than 40 cationic, anionic, nonionic Zn, Mg, or metal-free or axially substituted silicon Pcs and compared them under standardized conditions. Their spectral and photophysical properties, interactions with bovine serum albumin, subcellular localization, and in vitro PDT efficacy in three human cancer cell lines were assessed. Structural features influencing PDT efficacy include their presence in the monomeric state through axial substitution (in silicon Pcs) or rigid bulky peripheral groups with the latter enhancing activity in cationic derivatives while reducing it in nonionic derivatives. Amphiphilic structures significantly improved the PDT efficacy, especially for nonionic and anionic Pcs. The results of this study provide clear design principles for the future development of highly efficient PSs for PDT.
{"title":"Identifying Structural Factors Governing the Photodynamic Activity of Phthalocyanines","authors":"Magdalena Kozlikova, Mary Angelia Alfred, Miloslav Machacek, Fabienne Dumoulin, Andrés de la Escosura, Tomasz Goslinski, Marie Halaskova, Jian-Dong Huang, Mei-Rong Ke, Saad Makhseed, Dariusz T. Mlynarczyk, Dennis K. P. Ng, Tomás Torres, Roy C. H. Wong, Petr Zimcik, Veronika Novakova","doi":"10.1021/acs.jmedchem.5c03090","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03090","url":null,"abstract":"Phthalocyanines (Pcs) are promising photosensitizers (PSs) for photodynamic therapy (PDT). However, the variability in experimental conditions in <i>in vitro</i> experiments among reported derivatives complicates clear comparisons. In this study, we systematically evaluated a diverse set of more than 40 cationic, anionic, nonionic Zn, Mg, or metal-free or axially substituted silicon Pcs and compared them under standardized conditions. Their spectral and photophysical properties, interactions with bovine serum albumin, subcellular localization, and <i>in vitro</i> PDT efficacy in three human cancer cell lines were assessed. Structural features influencing PDT efficacy include their presence in the monomeric state through axial substitution (in silicon Pcs) or rigid bulky peripheral groups with the latter enhancing activity in cationic derivatives while reducing it in nonionic derivatives. Amphiphilic structures significantly improved the PDT efficacy, especially for nonionic and anionic Pcs. The results of this study provide clear design principles for the future development of highly efficient PSs for PDT.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"28 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122291","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}
CpG oligodeoxynucleotides (CpG ODNs) are short, synthetically produced DNA molecules that serve as classic agonists of Toll-like receptor 9 (TLR9). They are known for their ability to combat infection, alleviate allergic responses, and inhibit tumor growth. However, free CpG is rapidly degraded by nucleases, distributes poorly, and accumulates minimally in tumors. To overcome these limitations, CpG was tethered to tumor-associated antigens or antibodies that engage Fcγ receptors on immune cells in previous studies. Here we redirected CpG toward myeloid cells via SIRPα, an innate immune checkpoint expressed in dendritic cells and macrophages that transmits “don’t-eat-me” signals upon binding tumor-expressed CD47. The conjugate potently matured bone marrow-derived dendritic cells in vitro and, after simple intraperitoneal delivery, safely suppressed tumor growth in vivo. This myeloid-targeted CpG platform broadens the design space for TLR9 agonists and offers an off-the-shelf strategy for integrating innate and adaptive immunity against cancer.
{"title":"Modulation of Tumor Microenvironment via Antibody Mediated Precision Delivery of CpG to Myeloid Cell","authors":"Xiang Yu, Xiaoyao Hao, Hongyan Li, Zemeng Ma, Zhigang Ma, Liezhou Ji, Zhen Yang, Jialong Wang, Mingjiu Chen, Huricha Baigude","doi":"10.1021/acs.jmedchem.5c03629","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03629","url":null,"abstract":"CpG oligodeoxynucleotides (CpG ODNs) are short, synthetically produced DNA molecules that serve as classic agonists of Toll-like receptor 9 (TLR9). They are known for their ability to combat infection, alleviate allergic responses, and inhibit tumor growth. However, free CpG is rapidly degraded by nucleases, distributes poorly, and accumulates minimally in tumors. To overcome these limitations, CpG was tethered to tumor-associated antigens or antibodies that engage Fcγ receptors on immune cells in previous studies. Here we redirected CpG toward myeloid cells via SIRPα, an innate immune checkpoint expressed in dendritic cells and macrophages that transmits “don’t-eat-me” signals upon binding tumor-expressed CD47. The conjugate potently matured bone marrow-derived dendritic cells in vitro and, after simple intraperitoneal delivery, safely suppressed tumor growth in vivo. This myeloid-targeted CpG platform broadens the design space for TLR9 agonists and offers an off-the-shelf strategy for integrating innate and adaptive immunity against cancer.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"83 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122290","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}
Pub Date : 2026-02-06DOI: 10.1021/acs.jmedchem.5c02916
Matthew J Binder, Frances M Bashore, Kaitlin K Dunn Hoffman, Cameron Damgaard, Michael Slater, David H Drewry, Matthew B Robers, Alison D Axtman
A pivotal part of kinase chemical probe and drug development is assessment of the selectivity of a putative lead compound. While there is no consensus around the panel size or the type of assay(s) that are most appropriate, there is concurrence that gauging the number of on- and off-targets of a kinase inhibitor is essential. As pharmacology takes place in cells, we have compared profiling results for ten kinase inhibitors generated using the cell-free assays to those obtained when a panel of cellular target engagement NanoBRET assays is used to assess selectivity in intact cells. This is the first systematic comparison of these two approaches across a broad kinase panel. Comparison of the data sets demonstrates divergent results that can influence chemical probe prioritization. We identify unanticipated kinase interactions in cells for type II kinase inhibitors that are not observed in biochemical, cell-free systems. Furthermore, we characterize TPKI-39 as a DDR1, DDR2, and FLT1 chemical probe based on its in-cell selectivity profile.
{"title":"Cellular Context Influences Kinase Inhibitor Selectivity.","authors":"Matthew J Binder, Frances M Bashore, Kaitlin K Dunn Hoffman, Cameron Damgaard, Michael Slater, David H Drewry, Matthew B Robers, Alison D Axtman","doi":"10.1021/acs.jmedchem.5c02916","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02916","url":null,"abstract":"<p><p>A pivotal part of kinase chemical probe and drug development is assessment of the selectivity of a putative lead compound. While there is no consensus around the panel size or the type of assay(s) that are most appropriate, there is concurrence that gauging the number of on- and off-targets of a kinase inhibitor is essential. As pharmacology takes place in cells, we have compared profiling results for ten kinase inhibitors generated using the cell-free assays to those obtained when a panel of cellular target engagement NanoBRET assays is used to assess selectivity in intact cells. This is the first systematic comparison of these two approaches across a broad kinase panel. Comparison of the data sets demonstrates divergent results that can influence chemical probe prioritization. We identify unanticipated kinase interactions in cells for type II kinase inhibitors that are not observed in biochemical, cell-free systems. Furthermore, we characterize TPKI-39 as a DDR1, DDR2, and FLT1 chemical probe based on its in-cell selectivity profile.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146130571","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}
Pub Date : 2026-02-06DOI: 10.1021/acs.jmedchem.5c02552
Wenjian Zhu, Xiaojuan Chen, Xiaofei Li, Jieying Lin, Xiaojing Lin, Xueru Liu, Wuqing Deng, Xiaojuan Song, Zhengchao Tu, Adam V. Patterson, Jeff B. Smaill, Yongheng Chen, Xiaoyun Lu
Aberrant fibroblast growth factor receptor 3 (FGFR3) activation drives bladder carcinogenesis in humans, but currently approved pan-FGFR inhibitors lack FGFR3 isoform selectivity and fail to counter clinically acquired resistance mutations (e.g., FGFR3 V555M/L). Herein, we report the structure-based drug design of 4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine derivatives as the first covalent FGFR3 selective inhibitors. The representative compound 10s displayed high potency against FGFR3 (IC50 = 6.8 nM) and 5–60-fold selectivity over FGFR1/2/4. It was also effective against the common clinically acquired FGFR3V555M resistance mutation with an IC50 value of 19.2 nM. Furthermore, 10s exhibited strong antiproliferative effects in FGFR3-driven RT112/84 cells (IC50 = 9.2 nM). Structural characterization using MALDI-TOF-MS and X-ray crystallography confirmed covalent binding of 10s to FGFR3. Compound 10s also showed significant antitumor efficacy in the RT112/84 bladder cancer xenograft model, offering a promising compound to address both selectivity and resistance in FGFR3-targeted therapy.
{"title":"Structure-Based Design of 4-(1-Methyl-1H-indol-3-yl)pyrimidin-2-amine Derivatives as the First Covalent FGFR3 Selective Inhibitors","authors":"Wenjian Zhu, Xiaojuan Chen, Xiaofei Li, Jieying Lin, Xiaojing Lin, Xueru Liu, Wuqing Deng, Xiaojuan Song, Zhengchao Tu, Adam V. Patterson, Jeff B. Smaill, Yongheng Chen, Xiaoyun Lu","doi":"10.1021/acs.jmedchem.5c02552","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02552","url":null,"abstract":"Aberrant fibroblast growth factor receptor 3 (FGFR3) activation drives bladder carcinogenesis in humans, but currently approved pan-FGFR inhibitors lack FGFR3 isoform selectivity and fail to counter clinically acquired resistance mutations (e.g., FGFR3 V555M/L). Herein, we report the structure-based drug design of 4-(1-methyl-1<i>H</i>-indol-3-yl)pyrimidin-2-amine derivatives as the first covalent FGFR3 selective inhibitors. The representative compound <b>10s</b> displayed high potency against FGFR3 (IC<sub>50</sub> = 6.8 nM) and 5–60-fold selectivity over FGFR1/2/4. It was also effective against the common clinically acquired FGFR3<sup>V555M</sup> resistance mutation with an IC<sub>50</sub> value of 19.2 nM. Furthermore, <b>10s</b> exhibited strong antiproliferative effects in FGFR3-driven RT112/84 cells (IC<sub>50</sub> = 9.2 nM). Structural characterization using MALDI-TOF-MS and X-ray crystallography confirmed covalent binding of <b>10s</b> to FGFR3. Compound <b>10s</b> also showed significant antitumor efficacy in the RT112/84 bladder cancer xenograft model, offering a promising compound to address both selectivity and resistance in FGFR3-targeted therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122288","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}
Pub Date : 2026-02-05DOI: 10.1021/acs.jmedchem.5c02135
Niklas Piet Doering, Kristina Puls, Marta Diceglie, Anja Meraner, Axel Hentsch, Siriwat Hongnak, Armin Wurzer, Helmut Schmidhammer, Mariana Spetea, Marc Nazare, Gerhard Wolber
Opioids remain a cornerstone of pain management, but currently used therapeutics are associated with serious side effects. While κ-opioid receptor (KOR) agonists offer an alternative to classical μ-opioid receptor (MOR) agonists, their clinical potential is limited by severe adverse effects. G protein-biased KOR agonists are a promising strategy for developing safer analgesics. In this study, we used virtual screening to develop novel dual-charged naltrexamine amide derivatives as tool compounds for investigating biased agonism at the KOR. All of the predicted ligands demonstrate low-nanomolar activity and G protein bias at both the KOR and MOR. Molecular dynamics simulations revealed a key allosteric communication involving TM4, TM5, and ICL2. These compounds achieve their effects through interactions with residues E209ECL2, D2235.35, E2976.58, and K2275.39. These findings provide insight into the structural mechanisms of KOR signaling bias and inform the rational design of improved KOR therapeutics.
{"title":"Mechanistic Insights into G Protein-Biased κ-Opioid Receptor Signaling Using Dual-Charged Naltrexamine Amides","authors":"Niklas Piet Doering, Kristina Puls, Marta Diceglie, Anja Meraner, Axel Hentsch, Siriwat Hongnak, Armin Wurzer, Helmut Schmidhammer, Mariana Spetea, Marc Nazare, Gerhard Wolber","doi":"10.1021/acs.jmedchem.5c02135","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02135","url":null,"abstract":"Opioids remain a cornerstone of pain management, but currently used therapeutics are associated with serious side effects. While κ-opioid receptor (KOR) agonists offer an alternative to classical μ-opioid receptor (MOR) agonists, their clinical potential is limited by severe adverse effects. G protein-biased KOR agonists are a promising strategy for developing safer analgesics. In this study, we used virtual screening to develop novel dual-charged naltrexamine amide derivatives as tool compounds for investigating biased agonism at the KOR. All of the predicted ligands demonstrate low-nanomolar activity and G protein bias at both the KOR and MOR. Molecular dynamics simulations revealed a key allosteric communication involving TM4, TM5, and ICL2. These compounds achieve their effects through interactions with residues E209<sup>ECL2</sup>, D223<sup>5.35</sup>, E297<sup>6.58</sup>, and K227<sup>5.39</sup>. These findings provide insight into the structural mechanisms of KOR signaling bias and inform the rational design of improved KOR therapeutics.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"19 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146116008","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}
Pub Date : 2026-02-05DOI: 10.1021/acs.jmedchem.5c03240
Francesco Mastropasqua, Anna Teresa Lisi, Lucie Crouzier, Gabriella Rosanna Musillo, Francesca Serena Abatematteo, Mauro Niso, Benjamin Delprat, Nicola Antonio Colabufo, Vittoria Nanna, Giuseppe Felice Mangiatordi, Pietro Delre, Tina Spalholz, Matilde Colella, Winnie Deuther-Conrad, Fulvio Loiodice, Tangui Maurice, Antonio Laghezza, Carmen Abate
Sigma-1 receptor (S1R) is a “pluripotent chaperone” associated with pro-survival functions. Pieces of evidence show it as a promising therapeutic target for treating neurodegeneration. Encouraging results previously obtained with phenoxyalkylpiperidines prompted us to build a second generation of molecules using 1-[2-(4-chlorophenoxy)ethyl]-4-methylpiperidine (1), the most potent antiamnesic S1R ligand in vivo, as the lead-compound. Structural changes in the basic moiety and aromatic substitution were introduced, and features impacting on the S1R affinity and selectivity were clarified, also through docking studies and molecular dynamics (MD). The most promising phenoxyalkylpiperidines advanced to a phenotypic screening in wfs1abKO zebrafish larvae to assess hyperlocomotion reduction. Seven hit compounds were selected for the BiP–S1R dissociation as a measure of their agonist activity, followed by the preclinical evaluation of their activity against Alzheimer’s Disease (AD) in mice. These phenoxyethylpiperidines demonstrated to potently prevent AD-like amnesia without toxicity, appearing as promising agents for further preclinical studies against neurodegeneration.
{"title":"Development of Second-Generation Phenoxyethylpiperidines as Potent Sigma-1 Receptor Agonists with Neuroprotective Potential for Alzheimer’s Disease","authors":"Francesco Mastropasqua, Anna Teresa Lisi, Lucie Crouzier, Gabriella Rosanna Musillo, Francesca Serena Abatematteo, Mauro Niso, Benjamin Delprat, Nicola Antonio Colabufo, Vittoria Nanna, Giuseppe Felice Mangiatordi, Pietro Delre, Tina Spalholz, Matilde Colella, Winnie Deuther-Conrad, Fulvio Loiodice, Tangui Maurice, Antonio Laghezza, Carmen Abate","doi":"10.1021/acs.jmedchem.5c03240","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03240","url":null,"abstract":"Sigma-1 receptor (S1R) is a “pluripotent chaperone” associated with pro-survival functions. Pieces of evidence show it as a promising therapeutic target for treating neurodegeneration. Encouraging results previously obtained with phenoxyalkylpiperidines prompted us to build a second generation of molecules using 1-[2-(4-chlorophenoxy)ethyl]-4-methylpiperidine (<b>1</b>), the most potent antiamnesic S1R ligand in vivo, as the lead-compound. Structural changes in the basic moiety and aromatic substitution were introduced, and features impacting on the S1R affinity and selectivity were clarified, also through docking studies and molecular dynamics (MD). The most promising phenoxyalkylpiperidines advanced to a phenotypic screening in <i>wfs1ab</i><sup><i>KO</i></sup> zebrafish <i>larvae</i> to assess hyperlocomotion reduction. Seven hit compounds were selected for the BiP–S1R dissociation as a measure of their agonist activity, followed by the preclinical evaluation of their activity against Alzheimer’s Disease (AD) in mice. These phenoxyethylpiperidines demonstrated to potently prevent AD-like amnesia without toxicity, appearing as promising agents for further preclinical studies against neurodegeneration.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"302 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122293","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}
Pub Date : 2026-02-05DOI: 10.1021/acs.jmedchem.6c00267
Taher Uddin, Han Xie, Payal Mittal, Chloe Ence, Anil K. Gupta, Shrushti Patil, Christy Cho, Satavisha Banerjee, Amit Sharma, Bruno Melillo, Arnab K. Chatterjee, L. David Sibley
The following authors, Anil K. Gupta, Christy Cho, Satavisha Banerjee, have been added to the revised author list. Taher Uddin and Han Xie are co-first authors and contributed equally. This article has not yet been cited by other publications.
以下作者Anil K. Gupta, Christy Cho， Satavisha Banerjee已被添加到修订后的作者列表中。Taher Uddin和Han Xie是共同第一作者，贡献相同。这篇文章尚未被其他出版物引用。
{"title":"Correction to “Improved Bicyclic Pyrrolidine Analogues Inhibit Toxoplasma gondii Growth In Vitro and Cure Infection In Vivo”","authors":"Taher Uddin, Han Xie, Payal Mittal, Chloe Ence, Anil K. Gupta, Shrushti Patil, Christy Cho, Satavisha Banerjee, Amit Sharma, Bruno Melillo, Arnab K. Chatterjee, L. David Sibley","doi":"10.1021/acs.jmedchem.6c00267","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.6c00267","url":null,"abstract":"The following authors, Anil K. Gupta, Christy Cho, Satavisha Banerjee, have been added to the revised author list. Taher Uddin and Han Xie are co-first authors and contributed equally. This article has not yet been cited by other publications.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"47 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122317","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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