Pub Date : 2025-04-09DOI: 10.1021/acs.jmedchem.5c00295
Zhijie Deng, Jerrel Catlett, Youngeun Lee, Qiong Wu, Zhongli Xu, Ling Xie, Xian Chen, Yan Xiong, H. Ümit Kaniskan, Jian Jin
Proteolysis Targeting Chimeras (PROTACs) represent promising therapeutic modalities for degrading disease-causing proteins. However, the development of effective PROTACs has been limited by the availability of suitable E3 ligase ligands. In this study, we demonstrate for the first time that SPOP, an unexplored E3 ligase, can be recruited to degrade target proteins of interest. We developed a bridged PROTAC strategy and successfully discovered a proof-of-concept PROTAC degrader 9 (MS479), which recruits the E3 ligase SPOP by directly binding its substrate GLP as a bridge protein. This approach facilitates the polyubiquitination and subsequent degradation of BRD4/3/2 by the 26S proteasome. 9 effectively reduced the protein level of BRD4 short isoform in a time-, concentration-, GLP-, SPOP-, and ubiquitin-proteasome system (UPS)-dependent manner. Additionally, 9 effectively inhibited the proliferation of colorectal cancer (CRC) cells. Overall, our study expands the limited repertoire of the E3 ligases that can be harnessed for targeted protein degradation.
{"title":"Harnessing the SPOP E3 Ubiquitin Ligase via a Bridged Proteolysis Targeting Chimera (PROTAC) Strategy for Targeted Protein Degradation","authors":"Zhijie Deng, Jerrel Catlett, Youngeun Lee, Qiong Wu, Zhongli Xu, Ling Xie, Xian Chen, Yan Xiong, H. Ümit Kaniskan, Jian Jin","doi":"10.1021/acs.jmedchem.5c00295","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00295","url":null,"abstract":"Proteolysis Targeting Chimeras (PROTACs) represent promising therapeutic modalities for degrading disease-causing proteins. However, the development of effective PROTACs has been limited by the availability of suitable E3 ligase ligands. In this study, we demonstrate for the first time that SPOP, an unexplored E3 ligase, can be recruited to degrade target proteins of interest. We developed a bridged PROTAC strategy and successfully discovered a proof-of-concept PROTAC degrader <b>9</b> (MS479), which recruits the E3 ligase SPOP by directly binding its substrate GLP as a bridge protein. This approach facilitates the polyubiquitination and subsequent degradation of BRD4/3/2 by the 26S proteasome. <b>9</b> effectively reduced the protein level of BRD4 short isoform in a time-, concentration-, GLP-, SPOP-, and ubiquitin-proteasome system (UPS)-dependent manner. Additionally, <b>9</b> effectively inhibited the proliferation of colorectal cancer (CRC) cells. Overall, our study expands the limited repertoire of the E3 ligases that can be harnessed for targeted protein degradation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"245 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806171","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 : 2025-04-08DOI: 10.1021/acs.jmedchem.5c00383
Thuy Nguyen, Ann M. Decker, Daniel G. Barrus, Chi Hyuck Song, Jianfeng Liu, Thomas F. Gamage, Danni L. Harris, Jun-Xu Li, Yanan Zhang
Cannabinoid receptor type 1 (CB1) negative allosteric modulators have emerged as an alternate approach to CB1 orthosteric antagonists/inverse agonists for cocaine addiction treatment. This study explores aryl-alkyl squaramides as CB1 allosteric modulators, featuring RTICBM-262 (3) with good in vitro potencies in CB1 calcium mobilization, [35S]GTPγS binding, and cAMP assays. Molecular modeling studies suggest 3 bound in a similar pocket as Org27569, forming π-stacking with key residues H1542.41 and W2414.50, and the potential C98–C107 disulfide bond had limited impact on its binding or receptor activation. ADME and in vivo pharmacokinetic studies suggest that 3 had reasonable metabolic stability, brain penetration, and selectivity against a panel of ∼ 50 targets but poor solubility and high protein binding. At 5.6 mg/kg (i.p.), 3 significantly attenuated both cocaine-seeking behavior specific to cue-induced reinstatement and cocaine-induced behavioral sensitization without altering locomotor activity. These results support squaramides as promising candidates for further investigation for cocaine addiction treatment.
{"title":"Development of Squaramides as Allosteric Modulators of the CB1 Receptor: Synthesis, Computational Studies, Biological Characterization, and Effects against Cocaine-Induced Behavioral Sensitization and Reinstatement in Rats","authors":"Thuy Nguyen, Ann M. Decker, Daniel G. Barrus, Chi Hyuck Song, Jianfeng Liu, Thomas F. Gamage, Danni L. Harris, Jun-Xu Li, Yanan Zhang","doi":"10.1021/acs.jmedchem.5c00383","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00383","url":null,"abstract":"Cannabinoid receptor type 1 (CB<sub>1</sub>) negative allosteric modulators have emerged as an alternate approach to CB<sub>1</sub> orthosteric antagonists/inverse agonists for cocaine addiction treatment. This study explores aryl-alkyl squaramides as CB<sub>1</sub> allosteric modulators, featuring RTICBM-262 (<b>3</b>) with good in vitro potencies in CB<sub>1</sub> calcium mobilization, [<sup>35</sup>S]GTPγS binding, and cAMP assays. Molecular modeling studies suggest <b>3</b> bound in a similar pocket as Org27569, forming π-stacking with key residues H154<sup>2.41</sup> and W241<sup>4.50</sup>, and the potential C98–C107 disulfide bond had limited impact on its binding or receptor activation. ADME and in vivo pharmacokinetic studies suggest that <b>3</b> had reasonable metabolic stability, brain penetration, and selectivity against a panel of ∼ 50 targets but poor solubility and high protein binding. At 5.6 mg/kg (i.p.), <b>3</b> significantly attenuated both cocaine-seeking behavior specific to cue-induced reinstatement and cocaine-induced behavioral sensitization without altering locomotor activity. These results support squaramides as promising candidates for further investigation for cocaine addiction treatment.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"14 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143798436","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}
Hematologic malignancies represent the most prevalent type of malignant cancers associated with significant morbidity and mortality rates. Given CDK9’s extensive crosstalk with various signaling pathways and its crucial role in maintaining stem cell phenotypes, it emerges as a promising therapeutic target for hematologic malignancies. Despite ongoing efforts, resistance remains a ubiquitous challenge and significant limitation in the management of these malignancies. Here, we discovered a novel potent and selective inhibitor (14) of both CDK9 wild-type and L156F mutant, which inhibited p-Ser2 RNA Pol II, cMYC, and MCL-1, ultimately triggering apoptosis of hematological cancer cells. In vitro studies further revealed that 14 could efficiently suppress the proliferation of a diverse range of hematological cancer cell lines. Additionally, the in vivo efficacies have been demonstrated in different genetic background hematologic cancer cell-derived mice models. Together, these findings highlight the promising potential of this novel CDK9 inhibitor in the treatment of hematological malignancies.
{"title":"Discovery of a Novel Dihydroisoquinolinone Derivative as a Potent CDK9 Inhibitor Capable of Overcoming L156F Mutant for the Treatment of Hematologic Malignancies","authors":"Chenliang Shi, Yun Wu, Fengming Zou, Yuan Yuan, Chen Hu, Qingwang Liu, Chao Wu, Lijuan Shen, Aoli Wang, Wenchao Wang, Beilei Wang, Jing Liu, Qingsong Liu","doi":"10.1021/acs.jmedchem.4c02548","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02548","url":null,"abstract":"Hematologic malignancies represent the most prevalent type of malignant cancers associated with significant morbidity and mortality rates. Given CDK9’s extensive crosstalk with various signaling pathways and its crucial role in maintaining stem cell phenotypes, it emerges as a promising therapeutic target for hematologic malignancies. Despite ongoing efforts, resistance remains a ubiquitous challenge and significant limitation in the management of these malignancies. Here, we discovered a novel potent and selective inhibitor (<b>14</b>) of both CDK9 wild-type and L156F mutant, which inhibited p-Ser2 RNA Pol II, cMYC, and MCL-1, ultimately triggering apoptosis of hematological cancer cells. In vitro studies further revealed that <b>14</b> could efficiently suppress the proliferation of a diverse range of hematological cancer cell lines. Additionally, the in vivo efficacies have been demonstrated in different genetic background hematologic cancer cell-derived mice models. Together, these findings highlight the promising potential of this novel CDK9 inhibitor in the treatment of hematological malignancies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"14 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806172","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 : 2025-04-08DOI: 10.1021/acs.jmedchem.5c00133
Bochuan Deng, Ping Su, Lu Cheng, Jiao Zhang, Xiang Zhang, Tingli Yu, Guangjun Bao, Tiantian Yan, Yue Yin, Lei Shen, Dan Wang, Liang Hong, Xiaokang Miao, Wenle Yang, Chenyu Wang, Junqiu Xie, Rui Wang
Renal fibrosis, resulting from myofibroblast-mediated excessive extracellular matrix (ECM) deposition, lacks effective treatments. Novel peptide DR3penA developed by our group showed therapeutic potential for fibrotic diseases; however, its application was hindered by poor stability and bioavailability. To address this unmet need, we implemented stepwise optimization of DR3penA. The conformationally restricted analogs designed via structural predictions enhanced both activity and stability. Through structure–activity relationship analysis and cleavage site mapping, introducing unnatural amino acids improved stability. Fatty acid modifications conferred fibroblast-selective cytotoxicity and improved pharmacokinetics. After several rounds of progressive modification, peptide 27 exhibited remarkable stability, with a 5.68-fold extended half-life compared to DR3penA. Following profibrotic stimuli, peptide 27 effectively inhibited myofibroblast activation, epithelial–mesenchymal transition, and ECM synthesis. It also attenuated renal fibrosis in a unilateral ureteral obstruction model. Our study leverages multiple modifications that integrate cell and animal models to identify peptide 27 as a promising candidate for renal fibrosis therapy.
{"title":"Iterative Optimization Yields Stapled Peptides with Superior Pharmacokinetics and Potency for Renal Fibrosis Treatment","authors":"Bochuan Deng, Ping Su, Lu Cheng, Jiao Zhang, Xiang Zhang, Tingli Yu, Guangjun Bao, Tiantian Yan, Yue Yin, Lei Shen, Dan Wang, Liang Hong, Xiaokang Miao, Wenle Yang, Chenyu Wang, Junqiu Xie, Rui Wang","doi":"10.1021/acs.jmedchem.5c00133","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00133","url":null,"abstract":"Renal fibrosis, resulting from myofibroblast-mediated excessive extracellular matrix (ECM) deposition, lacks effective treatments. Novel peptide DR3penA developed by our group showed therapeutic potential for fibrotic diseases; however, its application was hindered by poor stability and bioavailability. To address this unmet need, we implemented stepwise optimization of DR3penA. The conformationally restricted analogs designed via structural predictions enhanced both activity and stability. Through structure–activity relationship analysis and cleavage site mapping, introducing unnatural amino acids improved stability. Fatty acid modifications conferred fibroblast-selective cytotoxicity and improved pharmacokinetics. After several rounds of progressive modification, peptide <b>27</b> exhibited remarkable stability, with a 5.68-fold extended half-life compared to DR3penA. Following profibrotic stimuli, peptide <b>27</b> effectively inhibited myofibroblast activation, epithelial–mesenchymal transition, and ECM synthesis. It also attenuated renal fibrosis in a unilateral ureteral obstruction model. Our study leverages multiple modifications that integrate cell and animal models to identify peptide <b>27</b> as a promising candidate for renal fibrosis therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"74 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806176","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 : 2025-04-08DOI: 10.1021/acs.jmedchem.5c00114
Bo Chen, Xiaofeng Liu, Tong Mu, Jiasu Xu, Dan Zhao, Fabian Dey, Yang Tang, Zhiheng Xu, June Yang, Ke Huang, Chiho Li, Shuai Chen, Sining Zhu, Summer Wang, XiangYu Yao, Zhipeng Yan, Yifan Tu, Yu Dai, Hongxia Qiu, Juhao Yang, Tianyi Jiang, Yunyue Qi, Yi Li, Hong C. Shen, Wei Zhu, Xuefei Tan, Jun Wu
PKMYT1 is a crucial regulator of the cell cycle, particularly involved in the G2/M transition through the inhibitory phosphorylation of CDK1, and is a promising therapeutic target for cancer therapy. Data mining in the Roche kinome screen database identified a hit characterized by 100% PKMYT1 inhibitory activity at a 10 μM concentration, which was further validated with a PKMYT1 enzymatic assay showing double-digit nanomolar potency. The hit featured a quinolinone central core and a phenol headgroup. The replacement of the problematic phenol headgroup with an indazole moiety induced a flip in the kinase hinge cysteine and glycine residues, resulting in a series of derivatives with enhanced potency, superior kinome selectivity, and no GSH flag. Further structural fine-tuning led to the discovery of compound 36, a novel, selective, and potent PKMYT1 inhibitor with favorable oral pharmacokinetic profiles and promising in vivo antitumor efficacy.
{"title":"Discovery of Naphthyridinone Derivatives as Selective and Potent PKMYT1 Inhibitors with Antitumor Efficacy","authors":"Bo Chen, Xiaofeng Liu, Tong Mu, Jiasu Xu, Dan Zhao, Fabian Dey, Yang Tang, Zhiheng Xu, June Yang, Ke Huang, Chiho Li, Shuai Chen, Sining Zhu, Summer Wang, XiangYu Yao, Zhipeng Yan, Yifan Tu, Yu Dai, Hongxia Qiu, Juhao Yang, Tianyi Jiang, Yunyue Qi, Yi Li, Hong C. Shen, Wei Zhu, Xuefei Tan, Jun Wu","doi":"10.1021/acs.jmedchem.5c00114","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00114","url":null,"abstract":"PKMYT1 is a crucial regulator of the cell cycle, particularly involved in the G2/M transition through the inhibitory phosphorylation of CDK1, and is a promising therapeutic target for cancer therapy. Data mining in the Roche kinome screen database identified a hit characterized by 100% PKMYT1 inhibitory activity at a 10 μM concentration, which was further validated with a PKMYT1 enzymatic assay showing double-digit nanomolar potency. The hit featured a quinolinone central core and a phenol headgroup. The replacement of the problematic phenol headgroup with an indazole moiety induced a flip in the kinase hinge cysteine and glycine residues, resulting in a series of derivatives with enhanced potency, superior kinome selectivity, and no GSH flag. Further structural fine-tuning led to the discovery of compound <b>36</b>, a novel, selective, and potent PKMYT1 inhibitor with favorable oral pharmacokinetic profiles and promising in vivo antitumor efficacy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"38 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806175","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}
Cryptococcus neoformans infections pose a significant global health threat. This study introduces mesoricin, a novel dual-domain antimicrobial peptide (AMP) scaffold derived from Mesorhizobium sp. identified using an in silico quantitative antifungal activity index (AFI). The peptide structure comprises an α-helix domain, which disrupts microbial membranes but exhibits highly hemolytic activity, and a β-sheet domain, which targets intracellular energy metabolism and resilient pathways. Rational design through α-helix domain removal and AFI-guided mutations yielded a mesoricin variant with enhanced antifungal activity and reduced cytotoxicity. The optimized mesoricin exhibited broad-spectrum antifungal activity against various Cryptococcus and Candida species (MIC 8–16 μg/mL) while maintaining high biosafety (IC50 > 128 μg/mL against human cell lines). Particularly, the variant demonstrated enhanced fungicidal effects at sub-MIC levels and superior biofilm control capabilities compared to the prototype peptide. These findings highlight mesoricins as a promising scaffold for AMP development targeting Cryptococcus infections.
{"title":"Activity and Safety Optimization of Mesoricin: A Dual-Domain Antifungal Peptide from Mesorhizobium sp.","authors":"Hongwei Zhao, Simei Sun, Xiang Ding, Yiling Zhang, Boyan Li, Shuyu Wang, Guo Guo, Jin Zhang","doi":"10.1021/acs.jmedchem.4c02917","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02917","url":null,"abstract":"<i>Cryptococcus neoformans</i> infections pose a significant global health threat. This study introduces mesoricin, a novel dual-domain antimicrobial peptide (AMP) scaffold derived from <i>Mesorhizobium</i> sp. identified using an <i>in silico</i> quantitative antifungal activity index (AFI). The peptide structure comprises an α-helix domain, which disrupts microbial membranes but exhibits highly hemolytic activity, and a β-sheet domain, which targets intracellular energy metabolism and resilient pathways. Rational design through α-helix domain removal and AFI-guided mutations yielded a mesoricin variant with enhanced antifungal activity and reduced cytotoxicity. The optimized mesoricin exhibited broad-spectrum antifungal activity against various <i>Cryptococcus</i> and <i>Candida</i> species (MIC 8–16 μg/mL) while maintaining high biosafety (IC<sub>50</sub> > 128 μg/mL against human cell lines). Particularly, the variant demonstrated enhanced fungicidal effects at sub-MIC levels and superior biofilm control capabilities compared to the prototype peptide. These findings highlight mesoricins as a promising scaffold for AMP development targeting <i>Cryptococcus</i> infections.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"183 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806173","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 : 2025-04-08DOI: 10.1021/acs.jmedchem.4c03112
Jana Lemke, Nadine Mengers, Louis Schmidt, Lukas Schulig, Stefanie König, Pascal Rosendahl, Frieda-Marie Bartz, Ulrike Garscha, Patrick J. Bednarski, Andreas Link
The voltage-gated potassium channel KV7.2/3 is gaining attention for its association with several medical indications. While recently reported, potent compounds aimed to fill the therapeutic gap left by market-withdrawn activators, key physicochemical parameters did not meet the requirements of potential drug candidates. Targeting the membrane-located channel requires subtly balancing lipophilicity, activity, and aqueous solubility. This publication describes the lead optimization of a highly active compound toward optimized physicochemical parameters. Out of 42 newly synthesized compounds, 30 showed activity on KV7.2/3 channels, and 15 had also an increased solubility compared the to hit compound. The integration of a three-dimensional bulky structure and the probable onset of chameleonic behavior, led to a 20-fold solubility increase (S = 21.7 vs 1.1 μM) and only slightly reduced potency (pEC50 = 7.42 vs 7.96) for the lead. Additionally, the target engagement of the compound was theoretically enhanced by a reduction of membrane retention.
{"title":"Lead Optimization of Positive Allosteric KV7.2/3 Channel Modulators toward Improved Balance of Lipophilicity and Aqueous Solubility","authors":"Jana Lemke, Nadine Mengers, Louis Schmidt, Lukas Schulig, Stefanie König, Pascal Rosendahl, Frieda-Marie Bartz, Ulrike Garscha, Patrick J. Bednarski, Andreas Link","doi":"10.1021/acs.jmedchem.4c03112","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03112","url":null,"abstract":"The voltage-gated potassium channel K<sub>V</sub>7.2/3 is gaining attention for its association with several medical indications. While recently reported, potent compounds aimed to fill the therapeutic gap left by market-withdrawn activators, key physicochemical parameters did not meet the requirements of potential drug candidates. Targeting the membrane-located channel requires subtly balancing lipophilicity, activity, and aqueous solubility. This publication describes the lead optimization of a highly active compound toward optimized physicochemical parameters. Out of 42 newly synthesized compounds, 30 showed activity on K<sub>V</sub>7.2/3 channels, and 15 had also an increased solubility compared the to hit compound. The integration of a three-dimensional bulky structure and the probable onset of chameleonic behavior, led to a 20-fold solubility increase (<i>S</i> = 21.7 vs 1.1 μM) and only slightly reduced potency (pEC<sub>50</sub> = 7.42 vs 7.96) for the lead. Additionally, the target engagement of the compound was theoretically enhanced by a reduction of membrane retention.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"16 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143798433","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 : 2025-04-08DOI: 10.1021/acs.jmedchem.4c03185
Ningning Pang, Na Zhao, Chunmei An, Keqiang Li, Peiying Li, Naiyuan Wang, Jian Li, Xing Cheng, Nan Zheng, Dong Guo, Xiaochun Xiong
Renal fibrosis, a key progression of chronic kidney disease (CKD), remains a major challenge in nephrology, with no FDA-approved drugs specifically targeting this condition. Interleukin-11 (IL-11) has emerged as a potential therapeutic target for renal fibrosis. In this study, we identified the antifibrotic effects of a recombinant human IL-11 analogue, IL-11–6M, in a mouse model of unilateral ureteral obstruction (UUO). We generated additional IL-11–6M variants via an optimized Escherichia coli expression system, with one variant (D46C) exhibiting comparable efficacy. Further modified through cysteine-specific PEGylation, analogue 13 demonstrated similar potency to IL-11–6M with an IC50 value of 61.5 ± 26.2 nM and maintained strong binding affinity to IL-11Rα (KD = 3.0 nM). Notably, analogue 13 exhibited a prolonged half-life and showed significant therapeutic effects in the UUO-induced renal fibrosis model. These findings suggest analogue 13 should be a promising candidate for the treatment of renal fibrosis.
{"title":"Development of a Long-Acting Interleukin-11 Antagonist for the Treatment of Renal Fibrosis","authors":"Ningning Pang, Na Zhao, Chunmei An, Keqiang Li, Peiying Li, Naiyuan Wang, Jian Li, Xing Cheng, Nan Zheng, Dong Guo, Xiaochun Xiong","doi":"10.1021/acs.jmedchem.4c03185","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03185","url":null,"abstract":"Renal fibrosis, a key progression of chronic kidney disease (CKD), remains a major challenge in nephrology, with no FDA-approved drugs specifically targeting this condition. Interleukin-11 (IL-11) has emerged as a potential therapeutic target for renal fibrosis. In this study, we identified the antifibrotic effects of a recombinant human IL-11 analogue, <b>IL-11–6M</b>, in a mouse model of unilateral ureteral obstruction (UUO). We generated additional <b>IL-11–6M</b> variants via an optimized <i>Escherichia coli</i> expression system, with one variant (D46C) exhibiting comparable efficacy. Further modified through cysteine-specific PEGylation, analogue <b>13</b> demonstrated similar potency to <b>IL-11–6M</b> with an IC<sub>50</sub> value of 61.5 ± 26.2 nM and maintained strong binding affinity to IL-11Rα (<i>K</i><sub>D</sub> = 3.0 nM). Notably, analogue <b>13</b> exhibited a prolonged half-life and showed significant therapeutic effects in the UUO-induced renal fibrosis model. These findings suggest analogue <b>13</b> should be a promising candidate for the treatment of renal fibrosis.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"93 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806174","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 : 2025-04-08DOI: 10.1021/acs.jmedchem.5c00377
Thomas D. Emmerich, Eleanor J. Taylor-Chilton, Elena Caballero, Iryna Hushcha, Kathryn Dickens, Izabela Stasik, Jane Alder, Santiago Saavedra-Castano, Erwin Berenschot, Niels R. Tas, Arturo Susarrey-Arce, Loreto Martinez-Gonzalez, Alina Oknianska, Tamara Zwain, Ana Martinez, Joseph M. Hayes
Glycogen synthase kinase-3 (GSK-3) is linked with multiple CNS conditions, including glioblastoma (GBM). Compared to the GSK-3β isoform, structure-based inhibitor design targeting GSK-3α is limited. Virtual screening was employed to identify GSK-3α inhibitors with CNS-active potential. Using a GSK-3α homology model, an optimized protocol with three-dimensional (3D)-pharmacophore filtering and Glide-SP docking was used to screen the ZINC20 biogenic subset. From 14 compounds selected for binding assay validation, three novel hit compounds were identified, with 1 (4-phenyl-1H-benzofuro[3,2-b]pyrazolo[4,3-e]pyridine scaffold) exhibiting nanomolar activity against GSK-3α/β (IC50s ∼ 0.26 μM). Selectivity profiling (12 homologous kinases) revealed selectivity for GSK-3α/β and protein kinase A (PKA). Compound 1 was more potent against three GBM cell lines (cell viability IC50s = 3–6 μM at 72 h) compared to benchmark GSK-3 inhibitor, 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), and nontoxic to human astrocytes. It demonstrated CNS-active potential in an all-human in vitro blood–brain barrier GBM model, good in vitro metabolic stability, excellent predicted oral bioavailability and represents a promising lead compound for development.
{"title":"Structure-Based Discovery Targeting GSK-3α Reveals Potent Nanomolar Selective 4-Phenyl-1H-benzofuro[3,2-b]pyrazolo[4,3-e]pyridine Inhibitor with Promising Glioblastoma and CNS-Active Potential in Cellular Models","authors":"Thomas D. Emmerich, Eleanor J. Taylor-Chilton, Elena Caballero, Iryna Hushcha, Kathryn Dickens, Izabela Stasik, Jane Alder, Santiago Saavedra-Castano, Erwin Berenschot, Niels R. Tas, Arturo Susarrey-Arce, Loreto Martinez-Gonzalez, Alina Oknianska, Tamara Zwain, Ana Martinez, Joseph M. Hayes","doi":"10.1021/acs.jmedchem.5c00377","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00377","url":null,"abstract":"Glycogen synthase kinase-3 (GSK-3) is linked with multiple CNS conditions, including glioblastoma (GBM). Compared to the GSK-3β isoform, structure-based inhibitor design targeting GSK-3α is limited. Virtual screening was employed to identify GSK-3α inhibitors with CNS-active potential. Using a GSK-3α homology model, an optimized protocol with three-dimensional (3D)-pharmacophore filtering and Glide-SP docking was used to screen the ZINC20 biogenic subset. From 14 compounds selected for binding assay validation, three novel hit compounds were identified, with <b>1</b> (4-phenyl-1<i>H</i>-benzofuro[3,2-<i>b</i>]pyrazolo[4,3-<i>e</i>]pyridine scaffold) exhibiting nanomolar activity against GSK-3α/β (IC<sub>50</sub>s ∼ 0.26 μM). Selectivity profiling (12 homologous kinases) revealed selectivity for GSK-3α/β and protein kinase A (PKA). Compound <b>1</b> was more potent against three GBM cell lines (cell viability IC<sub>50</sub>s = 3–6 μM at 72 h) compared to benchmark GSK-3 inhibitor, 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), and nontoxic to human astrocytes. It demonstrated CNS-active potential in an all-human <i>in vitro</i> blood–brain barrier GBM model, good <i>in vitro</i> metabolic stability, excellent predicted oral bioavailability and represents a promising lead compound for development.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"217 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806178","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 : 2025-04-08DOI: 10.1021/acs.jmedchem.5c00592
Ranjan Kumar Acharyya, Rohan Kalyan Rej, Biao Hu, Zhixiang Chen, Dimin Wu, Jianfeng Lu, Hoda Metwally, Donna McEachern, Yu Wang, Wei Jiang, Longchuan Bai, Jelena Tošović, Christina L. Gersch, Guozhang Xu, Weihong Zhang, WenXue Wu, E. Scott Priestley, Zhihua Sui, Farzad Sarkari, Bo Wen, Duxin Sun, James M. Rae, Shaomeng Wang
The compound structure in the graphical abstract of the original publication was incorrect. A corrected graphical abstract is included in this correction. This article has not yet been cited by other publications.
{"title":"Correction to “Discovery of ERD-1233 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader for the Treatment of ER+ Human Breast Cancer”","authors":"Ranjan Kumar Acharyya, Rohan Kalyan Rej, Biao Hu, Zhixiang Chen, Dimin Wu, Jianfeng Lu, Hoda Metwally, Donna McEachern, Yu Wang, Wei Jiang, Longchuan Bai, Jelena Tošović, Christina L. Gersch, Guozhang Xu, Weihong Zhang, WenXue Wu, E. Scott Priestley, Zhihua Sui, Farzad Sarkari, Bo Wen, Duxin Sun, James M. Rae, Shaomeng Wang","doi":"10.1021/acs.jmedchem.5c00592","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00592","url":null,"abstract":"The compound structure in the graphical abstract of the original publication was incorrect. A corrected graphical abstract is included in this correction.<img alt=\"\" src=\"/cms/10.1021/acs.jmedchem.5c00592/asset/images/medium/jm5c00592_0001.gif\"/> This article has not yet been cited by other publications.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"108 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143806177","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}
This article has not yet been cited by other publications.
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：