Journal of Medicinal Chemistry最新文献_第9页

Broad Target Screening Reveals Abundance of FKBP12-Based Molecular Glues in Focused Libraries 广泛的靶标筛选揭示了fkbp12分子胶在重点文库中的丰度

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-04-28 DOI: 10.1021/acs.jmedchem.5c00220

Johannes K. Dreizler, Christian Meyners, Wisely Oki Sugiarto, Maximilian L. Repity, Edvaldo V. S. Maciel, Patrick L. Purder, Frederik Lermyte, Stefan Knapp, Felix Hausch

{"title":"Broad Target Screening Reveals Abundance of FKBP12-Based Molecular Glues in Focused Libraries","authors":"Johannes K. Dreizler, Christian Meyners, Wisely Oki Sugiarto, Maximilian L. Repity, Edvaldo V. S. Maciel, Patrick L. Purder, Frederik Lermyte, Stefan Knapp, Felix Hausch","doi":"10.1021/acs.jmedchem.5c00220","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00220","url":null,"abstract":"Competitive (nondegradative) molecular glues represent a promising drug modality that remains underexplored primarily due to the lack of adequate hit identification approaches. In this study, we screened our historically grown FKBP-focused library containing >1000 drug-like molecules to identify FKBP-assisted molecular glues targeting a diverse panel of 57 proteins. In addition to establishing a robust and generalizable screening approach, we discovered three novel FKBP-dependent molecular glues targeting PTPRN, BRD4BD2, and STAT4. Our results demonstrate that molecular glues are more common than previously thought and that they can be identified by repurposing existing focused libraries. An optimized, highly cooperative FKBP12-BRD4BD2 glue demonstrated the involvement of the BD2 pocket and exhibited selectivity over the closely related BD1 domain. Our results underscore the value of FKBP12-assisted molecular glues to target challenging proteins with the potential for high selectivity.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"140 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880861","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}

引用次数: 0

Exploring the Phototherapeutic Applications of Mitochondria-Targeted COUPY Photocages of Antitumor Drugs 线粒体靶向抗肿瘤药物COUPY光笼的光疗应用探讨

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-04-28 DOI: 10.1021/acs.jmedchem.5c0055010.1021/acs.jmedchem.5c00550

Marta López-Corrales, Eduardo Izquierdo-García, Manel Bosch, Tapas Das, Amadeu Llebaria, Laia Josa-Culleré and Vicente Marchán*,

{"title":"Exploring the Phototherapeutic Applications of Mitochondria-Targeted COUPY Photocages of Antitumor Drugs","authors":"Marta López-Corrales, Eduardo Izquierdo-García, Manel Bosch, Tapas Das, Amadeu Llebaria, Laia Josa-Culleré and Vicente Marchán*, ","doi":"10.1021/acs.jmedchem.5c0055010.1021/acs.jmedchem.5c00550","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00550https://doi.org/10.1021/acs.jmedchem.5c00550","url":null,"abstract":"Photocleavable protecting groups hold great promise in photopharmacology to control the release of bioactive molecules from their caged precursors within specific subcellular compartments. Herein, we describe a series of photocages based on a COUPY scaffold, incorporating chlorambucil (CLB) and 4-phenylbutyric acid (4-PBA) as bioactive payloads that can be efficiently activated with visible light. Confocal microscopy confirmed the preferential accumulation of CLB and 4-PBA N-hexyl COUPY photocages in the mitochondria, which exhibited a remarkable phototoxicity against cancer cells upon green-yellow light irradiation, with IC50 values in the nanomolar range. This effect was attributed to a synergistic mechanism involving the photorelease of the bioactive payloads and the intrinsic photogeneration of Type I and Type II ROS by the COUPY scaffold within mitochondria. Thus, COUPY-caged derivatives of CLB and 4-PBA underscore the potential of COUPY-caging groups as a versatile platform to develop innovative light-activated agents operating simultaneously through photodynamic therapy and photoactivated chemotherapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 9","pages":"9741–9754 9741–9754"},"PeriodicalIF":6.8,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917002","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}

引用次数: 0

Discovery of Potent PDEδ/NAMPT Dual Inhibitors: Preclinical Evaluation in KRAS Mutant Pancreatic Cancer Cells 发现有效的PDEδ/NAMPT双重抑制剂：KRAS突变胰腺癌细胞的临床前评估

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-04-27 DOI: 10.1021/acs.jmedchem.4c02636

Yaojin Zhu, Zhenqian Chen, Guoyuan Wu, Yuxin Fang, Yuhan Bao, Jiayi Zhu, Guoqiang Dong, Chunquan Sheng, Shipeng He

{"title":"Discovery of Potent PDEδ/NAMPT Dual Inhibitors: Preclinical Evaluation in KRAS Mutant Pancreatic Cancer Cells","authors":"Yaojin Zhu, Zhenqian Chen, Guoyuan Wu, Yuxin Fang, Yuhan Bao, Jiayi Zhu, Guoqiang Dong, Chunquan Sheng, Shipeng He","doi":"10.1021/acs.jmedchem.4c02636","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02636","url":null,"abstract":"Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations are a common type of oncogenic mutation, widely observed in various cancers. The trafficking chaperone PDE6D (or PDEδ) has been proposed as an alternative target for KRAS, which has led to the preclinical evaluation of PDEδ inhibitors for targeting KRAS mutant cancers. In this study, inspired by the synergistic effect between PDEδ and nicotinamide phosphoribosyl transferase (NAMPT), we report the discovery of the first PDEδ/NAMPT dual inhibitors, which may serve as an interesting starting point for targeting KRAS mutant pancreatic cancer cell lines (MiaPaca-2). Among these, a highly potent dual inhibitor (17d) was identified, exhibiting balanced and robust activity against PDEδ (KD = 0.410 nM) and NAMPT (IC50 = 2.21 nM). Notably, 17d demonstrated superior antitumor efficacy both in vitro and in vivo compared to either PDEδ or NAMPT inhibitors alone or in combination, highlighting the potential of PDEδ/NAMPT dual inhibitors in treating KRAS mutant pancreatic cancer cell lines.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"253 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880862","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}

引用次数: 0

Discovery of Potent PDEδ/NAMPT Dual Inhibitors: Preclinical Evaluation in KRAS Mutant Pancreatic Cancer Cells 发现有效的PDEδ/NAMPT双重抑制剂：KRAS突变胰腺癌细胞的临床前评估

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-04-27 DOI: 10.1021/acs.jmedchem.4c0263610.1021/acs.jmedchem.4c02636

Yaojin Zhu, Zhenqian Chen, Guoyuan Wu, Yuxin Fang, Yuhan Bao, Jiayi Zhu, Guoqiang Dong*, Chunquan Sheng* and Shipeng He*,

{"title":"Discovery of Potent PDEδ/NAMPT Dual Inhibitors: Preclinical Evaluation in KRAS Mutant Pancreatic Cancer Cells","authors":"Yaojin Zhu, Zhenqian Chen, Guoyuan Wu, Yuxin Fang, Yuhan Bao, Jiayi Zhu, Guoqiang Dong*, Chunquan Sheng* and Shipeng He*, ","doi":"10.1021/acs.jmedchem.4c0263610.1021/acs.jmedchem.4c02636","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02636https://doi.org/10.1021/acs.jmedchem.4c02636","url":null,"abstract":"Kirsten rat sarcoma viral oncogene homologue (KRAS) mutations are a common type of oncogenic mutation, widely observed in various cancers. The trafficking chaperone PDE6D (or PDEδ) has been proposed as an alternative target for KRAS, which has led to the preclinical evaluation of PDEδ inhibitors for targeting KRAS mutant cancers. In this study, inspired by the synergistic effect between PDEδ and nicotinamide phosphoribosyl transferase (NAMPT), we report the discovery of the first PDEδ/NAMPT dual inhibitors, which may serve as an interesting starting point for targeting KRAS mutant pancreatic cancer cell lines (MiaPaca-2). Among these, a highly potent dual inhibitor (17d) was identified, exhibiting balanced and robust activity against PDEδ (KD = 0.410 nM) and NAMPT (IC50 = 2.21 nM). Notably, 17d demonstrated superior antitumor efficacy both in vitro and in vivo compared to either PDEδ or NAMPT inhibitors alone or in combination, highlighting the potential of PDEδ/NAMPT dual inhibitors in treating KRAS mutant pancreatic cancer cell lines.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 9","pages":"9241–9259 9241–9259"},"PeriodicalIF":6.8,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917215","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}

引用次数: 0

Drug-like Antagonists of P2Y Receptor Subtypes: An Update P2Y受体亚型的药物样拮抗剂：最新进展

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-04-27 DOI: 10.1021/acs.jmedchem.5c00249

Mahesh Puthanveedu, Rebecca Knight, Michael J. Stocks

{"title":"Drug-like Antagonists of P2Y Receptor Subtypes: An Update","authors":"Mahesh Puthanveedu, Rebecca Knight, Michael J. Stocks","doi":"10.1021/acs.jmedchem.5c00249","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00249","url":null,"abstract":"The hunt for drug-like P2YR antagonists continues, stimulated by ever-increasing pharmacological evidence for their clinical benefit and the astonishing array of biological functions which they orchestrate, including platelet aggregation, cancer proliferation, pain, neurodegenerative diseases, and immune regulation. Extensive research has identified modulators of P2Y receptors. However, only a limited number of small-molecule antagonists for the P2Y12 receptor have received approval for their clinical use. Recent pioneering discoveries of small-molecule ligand-bound X-ray crystal structures for the P2Y1 and P2Y12 receptors and homology modeling has stimulated research groups to explore orthosteric and allosteric receptor antagonists, aided in part by the discovery of fluorescent P2YR imaging tools and sensitive screening methods that allow the identification of low affinity P2Y receptor antagonists. This Perspective critically assesses P2Y receptor antagonists published since 2016, highlighting potential oral lead- or drug-like compounds that offer opportunities for the development of molecules for clinical evaluation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"53 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880864","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}

引用次数: 0

Drug-like Antagonists of P2Y Receptor Subtypes: An Update P2Y受体亚型的药物样拮抗剂：最新进展

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-04-27 DOI: 10.1021/acs.jmedchem.5c0024910.1021/acs.jmedchem.5c00249

Mahesh Puthanveedu, Rebecca Knight and Michael J. Stocks*,

{"title":"Drug-like Antagonists of P2Y Receptor Subtypes: An Update","authors":"Mahesh Puthanveedu, Rebecca Knight and Michael J. Stocks*, ","doi":"10.1021/acs.jmedchem.5c0024910.1021/acs.jmedchem.5c00249","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00249https://doi.org/10.1021/acs.jmedchem.5c00249","url":null,"abstract":"The hunt for drug-like P2YR antagonists continues, stimulated by ever-increasing pharmacological evidence for their clinical benefit and the astonishing array of biological functions which they orchestrate, including platelet aggregation, cancer proliferation, pain, neurodegenerative diseases, and immune regulation. Extensive research has identified modulators of P2Y receptors. However, only a limited number of small-molecule antagonists for the P2Y12 receptor have received approval for their clinical use. Recent pioneering discoveries of small-molecule ligand-bound X-ray crystal structures for the P2Y1 and P2Y12 receptors and homology modeling has stimulated research groups to explore orthosteric and allosteric receptor antagonists, aided in part by the discovery of fluorescent P2YR imaging tools and sensitive screening methods that allow the identification of low affinity P2Y receptor antagonists. This Perspective critically assesses P2Y receptor antagonists published since 2016, highlighting potential oral lead- or drug-like compounds that offer opportunities for the development of molecules for clinical evaluation.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 9","pages":"9057–9083 9057–9083"},"PeriodicalIF":6.8,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.jmedchem.5c00249","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917218","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}

引用次数: 0

Targeting SleC and CspB in the Inhibition of Spore Germination in Clostridioides difficile 以SleC和CspB为靶点抑制艰难梭菌孢子萌发

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-04-26 DOI: 10.1021/acs.jmedchem.4c0309010.1021/acs.jmedchem.4c03090

Jingdong Yang, Yuanyuan Qian, Choon Kim, Biruk T. Birhanu, Carlos Cal y Mayor-Luna, Derong Ding, Xiaotan Yu, Valerie A. Schroeder, Shahriar Mobashery and Mayland Chang*,

{"title":"Targeting SleC and CspB in the Inhibition of Spore Germination in Clostridioides difficile","authors":"Jingdong Yang, Yuanyuan Qian, Choon Kim, Biruk T. Birhanu, Carlos Cal y Mayor-Luna, Derong Ding, Xiaotan Yu, Valerie A. Schroeder, Shahriar Mobashery and Mayland Chang*, ","doi":"10.1021/acs.jmedchem.4c0309010.1021/acs.jmedchem.4c03090","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03090https://doi.org/10.1021/acs.jmedchem.4c03090","url":null,"abstract":"Clostridioides difficile, a Gram-positive, spore-forming anaerobic bacterium, is a major healthcare threat. Its spores colonize the gut following dysbiosis caused by broad-spectrum antibiotics, remaining dormant until host’s bile acid triggers germination into vegetative cells that produce toxins, leading to diarrhea, colitis, and potentially death. Current antibiotics to treat C. difficile infection target vegetative cells but not spore germination, a pivotal step in infection development. This study unveils 1,2,4-oxadiazoles as a novel class of spore germination inhibitors and delineates the structure–activity relationship. Screening of 120 oxadiazoles revealed compound 110 (IC50 = 14 ± 1 μM or 6.3 ± 0.4 μg/mL). Compound 110 targets mature SleC (Kd = 12 ± 1.0 μM) and CspB (Kd = 8.0 ± 1.0 μM) on spores, inhibiting their enzymatic activities, thus preventing spore germination. To our knowledge, compound 110 is the first reported spore germination inhibitor targeting SleC/CspB, offering a promising avenue for C. difficile therapies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 9","pages":"9357–9370 9357–9370"},"PeriodicalIF":6.8,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917212","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}

引用次数: 0

Targeting SleC and CspB in the Inhibition of Spore Germination in Clostridioides difficile 以SleC和CspB为靶点抑制艰难梭菌孢子萌发

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-04-26 DOI: 10.1021/acs.jmedchem.4c03090

Jingdong Yang, Yuanyuan Qian, Choon Kim, Biruk T. Birhanu, Carlos Cal y Mayor-Luna, Derong Ding, Xiaotan Yu, Valerie A. Schroeder, Shahriar Mobashery, Mayland Chang

{"title":"Targeting SleC and CspB in the Inhibition of Spore Germination in Clostridioides difficile","authors":"Jingdong Yang, Yuanyuan Qian, Choon Kim, Biruk T. Birhanu, Carlos Cal y Mayor-Luna, Derong Ding, Xiaotan Yu, Valerie A. Schroeder, Shahriar Mobashery, Mayland Chang","doi":"10.1021/acs.jmedchem.4c03090","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03090","url":null,"abstract":"Clostridioides difficile, a Gram-positive, spore-forming anaerobic bacterium, is a major healthcare threat. Its spores colonize the gut following dysbiosis caused by broad-spectrum antibiotics, remaining dormant until host’s bile acid triggers germination into vegetative cells that produce toxins, leading to diarrhea, colitis, and potentially death. Current antibiotics to treat C. difficile infection target vegetative cells but not spore germination, a pivotal step in infection development. This study unveils 1,2,4-oxadiazoles as a novel class of spore germination inhibitors and delineates the structure–activity relationship. Screening of 120 oxadiazoles revealed compound 110 (IC50 = 14 ± 1 μM or 6.3 ± 0.4 μg/mL). Compound 110 targets mature SleC (Kd = 12 ± 1.0 μM) and CspB (Kd = 8.0 ± 1.0 μM) on spores, inhibiting their enzymatic activities, thus preventing spore germination. To our knowledge, compound 110 is the first reported spore germination inhibitor targeting SleC/CspB, offering a promising avenue for C. difficile therapies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"7 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878033","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}

引用次数: 0

Discovery of Novel, Potent, and Orally Bioavailable SMARCA2 Proteolysis-Targeting Chimeras with Synergistic Antitumor Activity in Combination with Kirsten Rat Sarcoma Viral Oncogene Homologue G12C Inhibitors 新型有效的口服生物可利用的靶向SMARCA2蛋白水解的嵌合体与Kirsten大鼠肉瘤病毒癌基因同源物G12C抑制剂联合具有协同抗肿瘤活性

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-04-25 DOI: 10.1021/acs.jmedchem.4c02577

Sasikumar Kotagiri, Yawen Wang, Yanyan Han, Xiaobing Liang, Nicholas Blazanin, Hira Mazhar, Manu Sebastian, Phuong Kieu Nguyen, Yongying Jiang, Yonathan Lissanu

{"title":"Discovery of Novel, Potent, and Orally Bioavailable SMARCA2 Proteolysis-Targeting Chimeras with Synergistic Antitumor Activity in Combination with Kirsten Rat Sarcoma Viral Oncogene Homologue G12C Inhibitors","authors":"Sasikumar Kotagiri, Yawen Wang, Yanyan Han, Xiaobing Liang, Nicholas Blazanin, Hira Mazhar, Manu Sebastian, Phuong Kieu Nguyen, Yongying Jiang, Yonathan Lissanu","doi":"10.1021/acs.jmedchem.4c02577","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02577","url":null,"abstract":"Cancer genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex, including SMARCA4 in nonsmall cell lung cancer with a frequency of up to 33% in advanced-stage disease, making it the most frequently mutated complex. We and others have identified SMARCA2 to be synthetic lethal to SMARCA4, indicating that SMARCA2 is a high-value therapeutic target. Here, we disclose the discovery and characterization of potent, selective, and orally bioavailable cereblon-based SMARCA2 PROTACs. Biochemically, we showed that YDR1 and YD54 are potent SMARCA2 degraders. Further, we showed the antitumor growth inhibitory activity of YDR1 and YD54 in SMARCA4 mutant xenografts. Finally, we show that YDR1 and YD54 synergize with the KRAS G12C inhibitor sotorasib to inhibit the growth of SMARCA4 and KRAS G12C comutant lung cancer cells. These findings provide evidence for the utility of single agent or combination regimens containing SMARCA2 PROTACs as synthetic lethal therapeutics against SMARCA4 mutant cancers.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"7 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876373","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}

引用次数: 0

Discovery of Novel, Potent, and Orally Bioavailable SMARCA2 Proteolysis-Targeting Chimeras with Synergistic Antitumor Activity in Combination with Kirsten Rat Sarcoma Viral Oncogene Homologue G12C Inhibitors 新型有效的口服生物可利用的靶向SMARCA2蛋白水解的嵌合体与Kirsten大鼠肉瘤病毒癌基因同源物G12C抑制剂联合具有协同抗肿瘤活性

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2025-04-25 DOI: 10.1021/acs.jmedchem.4c0257710.1021/acs.jmedchem.4c02577

Sasikumar Kotagiri, Yawen Wang, Yanyan Han, Xiaobing Liang, Nicholas Blazanin, Hira Mazhar, Manu Sebastian, Phuong Kieu Nguyen, Yongying Jiang and Yonathan Lissanu*,

{"title":"Discovery of Novel, Potent, and Orally Bioavailable SMARCA2 Proteolysis-Targeting Chimeras with Synergistic Antitumor Activity in Combination with Kirsten Rat Sarcoma Viral Oncogene Homologue G12C Inhibitors","authors":"Sasikumar Kotagiri, Yawen Wang, Yanyan Han, Xiaobing Liang, Nicholas Blazanin, Hira Mazhar, Manu Sebastian, Phuong Kieu Nguyen, Yongying Jiang and Yonathan Lissanu*, ","doi":"10.1021/acs.jmedchem.4c0257710.1021/acs.jmedchem.4c02577","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02577https://doi.org/10.1021/acs.jmedchem.4c02577","url":null,"abstract":"Cancer genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex, including SMARCA4 in nonsmall cell lung cancer with a frequency of up to 33% in advanced-stage disease, making it the most frequently mutated complex. We and others have identified SMARCA2 to be synthetic lethal to SMARCA4, indicating that SMARCA2 is a high-value therapeutic target. Here, we disclose the discovery and characterization of potent, selective, and orally bioavailable cereblon-based SMARCA2 PROTACs. Biochemically, we showed that YDR1 and YD54 are potent SMARCA2 degraders. Further, we showed the antitumor growth inhibitory activity of YDR1 and YD54 in SMARCA4 mutant xenografts. Finally, we show that YDR1 and YD54 synergize with the KRAS G12C inhibitor sotorasib to inhibit the growth of SMARCA4 and KRAS G12C comutant lung cancer cells. These findings provide evidence for the utility of single agent or combination regimens containing SMARCA2 PROTACs as synthetic lethal therapeutics against SMARCA4 mutant cancers.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 9","pages":"9202–9219 9202–9219"},"PeriodicalIF":6.8,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.jmedchem.4c02577","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917126","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}

引用次数: 0