De-Xuan Hu, Chao Qin, Li-Shuang Guo, Wen-Ya Liu, Zi-Qiong Liang, Ye Cao, Chuan-Sheng Yao, Yingqi Wei, Xin Yue, Md Rasel Al Mahmud, Keli Agama, Huaiming Wang*, Yves Pommier* and Lin-Kun An*,
{"title":"Synthesis of 5,9- and 5,8-Diaminoalkoxy Substituted Benzophenanthridinone Analogues as Tyrosyl-DNA Phosphodiesterase 1 Inhibitors and Their Radiosensitizing Activity","authors":"De-Xuan Hu, Chao Qin, Li-Shuang Guo, Wen-Ya Liu, Zi-Qiong Liang, Ye Cao, Chuan-Sheng Yao, Yingqi Wei, Xin Yue, Md Rasel Al Mahmud, Keli Agama, Huaiming Wang*, Yves Pommier* and Lin-Kun An*, ","doi":"10.1021/acs.jmedchem.4c0295110.1021/acs.jmedchem.4c02951","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02951https://doi.org/10.1021/acs.jmedchem.4c02951","url":null,"abstract":"<p >Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a potential target for cancer chemotherapy and radiotherapy. There are a few reports on TDP1 inhibitors used in chemotherapy, but no report on their use in radiotherapy. Herein, we designed and synthesized a series of titled analogues. Twelve analogues showed high TDP1 inhibitory activity. Among them, <b>18</b> (IC<sub>50</sub> = 6.9 μM) showed strong radiosensitization in colorectal cancer cells, and could suppress tumor growth in the HCT116 xenograft animal model combined with X-ray radiation, and exhibited low acute toxicity with good pharmacokinetic (PK) parameters, implying that <b>18</b> is worth further clinical research. Further studies indicated that <b>18</b> could target cellular TDP1 and suppress NHEJ repair activity for radiation-induced DNA damage, resulting in cancer cell death. Additionally, <b>18</b> could also increase the expression of PIG3, resulting in an enhancement of radiation-induced cellular ROS and mitochondrial dysfunction. Our studies provide a novel cancer treatment strategy combining TDP1 inhibitors and radiotherapy.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 9","pages":"9323–9340 9323–9340"},"PeriodicalIF":6.8,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917180","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}
Shi Hou, Jiajia Chang, Cheng Xing, Ze Ye, Wei Li, Ying Zhang, Zhibing Zheng*, Junhai Xiao* and Song Li,
{"title":"Design, Synthesis, and Biological Evaluation of Selective STING Synergists That Enhance cGAMP-STING Pathway Activation without Inherent Agonist Activity","authors":"Shi Hou, Jiajia Chang, Cheng Xing, Ze Ye, Wei Li, Ying Zhang, Zhibing Zheng*, Junhai Xiao* and Song Li, ","doi":"10.1021/acs.jmedchem.4c0313110.1021/acs.jmedchem.4c03131","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03131https://doi.org/10.1021/acs.jmedchem.4c03131","url":null,"abstract":"<p >The cGAS-STING pathway is pivotal for innate immunity and antitumor responses. However, the challenge of selectively targeting the diseased tissue without harming the healthy tissue has impeded the development of STING agonists. In this article, we tackle this issue by developing novel STING synergists that target the STING C-terminal domain pocket. Our findings indicate that agonist <b>12B</b> can boost the cGAMP-STING pathway synergistically. Through reverse optimization of <b>12B</b>, we synthesized three series of compounds, with compounds <b>55</b>, <b>66</b>, and <b>67</b> emerging as selective STING synergists that amplify cGAMP-induced pathway activation without inherent agonist properties. Compound <b>67</b> emerged as the most potent (EC<sub>50</sub> = 20.53 μM), displaying a broad binding affinity across STING-CTD alleles and potent antitumor efficacy in vivo. Notably, it exhibited excellent safety profiles in both in vitro and in vivo models, along with favorable pharmacokinetics. These findings highlight the therapeutic potential of novel STING synergists for cancer immunotherapy.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 9","pages":"9407–9430 9407–9430"},"PeriodicalIF":6.8,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917226","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}
Paul S. Riehl, Meng Yao Zhang, Payal Dhar, Zhiying Wang, Jie Pan, Kathleen Mansfield, Walter L. Johnson, Qian Zhang, Yvonne Li, Ryan D’Souza, Jun Zhang, Jonathan Olsen, Madhura Deshpande, Srikanth Kotapati, Scott A. Hollingsworth, Isha Verma, Yi-xin Li, Yang Su, Qinqin Cheng, Sayumi Yamazoe, Luca Micci, Miranda Broz, James Janc, Eugene P. Chekler and Julian C. Lo*,
{"title":"Antibody-Drug Conjugates of NLRP3 Agonists: How Overcoming Lysosomal Accumulation Necessitated Noncanonical Linker Attachments","authors":"Paul S. Riehl, Meng Yao Zhang, Payal Dhar, Zhiying Wang, Jie Pan, Kathleen Mansfield, Walter L. Johnson, Qian Zhang, Yvonne Li, Ryan D’Souza, Jun Zhang, Jonathan Olsen, Madhura Deshpande, Srikanth Kotapati, Scott A. Hollingsworth, Isha Verma, Yi-xin Li, Yang Su, Qinqin Cheng, Sayumi Yamazoe, Luca Micci, Miranda Broz, James Janc, Eugene P. Chekler and Julian C. Lo*, ","doi":"10.1021/acs.jmedchem.5c0059610.1021/acs.jmedchem.5c00596","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00596https://doi.org/10.1021/acs.jmedchem.5c00596","url":null,"abstract":"<p >An initial series of NLRP3 agonist antibody-drug conjugates (ADCs) failed to induce IL-1β in vitro due to lysosomal trapping of the payload. To address this, we developed assays and computational tools to identify a new payload that could diffuse out of the lysosomes. ADCs derived from this payload were active, emphasizing the need to avoid payload lysosomal accumulation for nonlysosomal targets. Two active ADCs necessitated attaching a cleavable valine-citrulline recognition element to the payload via a noncanonical ester linkage, rather than a canonical carbamate one, since the payload did not contain a basic amine. The citrulline stereocenter configuration was found to affect the payload release and in vitro activity. The ADC with the (L)-Val-(L)-Cit ester configuration showed superior in vitro activity, high stability in mouse serum, and rapid cleavage in human liver lysosomes. These properties suggest that this noncanonical (L)-Val-(L)-Cit ester attachment may be valuable to the ADC community moving forward.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 9","pages":"9799–9810 9799–9810"},"PeriodicalIF":6.8,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917222","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":"Double Swords in One: Novel Selective PI3K/110β PROTAC Degraders for the Treatment of Multidrug-Resistant Cancer by Activating ERS and Inhibiting P-gp","authors":"Juan Cen, Ping Lu, Chenwei Wang, Jing Wu, Xiaojiao Hu, Han Zhao, Mengyu Li, Mingkai Luo, Shizhen Zhao, Xiaohui Li, Shaofeng Duan","doi":"10.1021/acs.jmedchem.4c03169","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03169","url":null,"abstract":"The p110β isoform of the PI3 kinase (PI3K) family plays a key role in tumorigenesis and PTEN loss-driven multidrug resistance (MDR). Herein, we describe the design, synthesis, and structure–activity relationship studies of a series of small-molecule PI3<i>K</i>/110β PROTACs degraders by combining the selective inhibitor TGX221 of PI3<i>K</i>/110β with VHL ligands. Among them, <b>J-6</b> and <b>J-9</b> exhibited rapid and efficient degradation ability for the target proteins in MDR cells. Meanwhile, the expression and activity of P-glycoprotein were significantly inhibited, leading to a strong synergistic antitumor effect with adriamycin or cisplatin. Further studies confirmed that the two degraders can induce endoplasmic reticulum stress-mediated mitochondrial apoptosis by the AKT/Bcl-2 inhibition-mediated PERK/CHOP-unfolded protein reaction. In vivo studies also verified that the two degraders inhibited the growth of MCF-7/ADM xenograft tumors with high safety. Hence, this study and further optimization of these PI3<i>K</i>/110β PROTAC degraders have broad prospects for the development of new cancer therapies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"44 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885400","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":"Design and Development of a Novel Oral 4′-Fluorouridine Double Prodrug VV261 against SFTSV","authors":"Yong Cheng, Wei Zheng, Xinru Dong, Tengxiao Sun, Mengwei Xu, Li Xiang, Jian Li, Huilong Wang, Xiaoqin Jian, Jingjin Yu, Pengcheng Li, Tianwen Hu, Guanghui Tian, Xiangrui Jiang, Leike Zhang, Haji A. Aisa, Yuanchao Xie, Gengfu Xiao, Jingshan Shen","doi":"10.1021/acs.jmedchem.5c00626","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00626","url":null,"abstract":"4′-Fluorouridine (4′-FU), despite demonstrating potent anti-SFTSV efficacy in vitro and in vivo, faces hindrances in its further development as a promising drug due to its weak chemical stability. Here, we report the discovery and development of VV261, a novel 4′-FU double prodrug with three isobutyryl groups on the ribose moiety and a nicotinoyloxymethyl group linked to the imide-nitrogen on the base moiety, exhibiting notable chemical stability and favorable pharmacokinetic properties. In SFTSV-infected mice, VV261 at 5 mg/kg/d for 7 days demonstrated complete protection against lethal SFTSV infection, prevented weight loss, and even a 2 day treatment significantly reduced both viral RNA copies and infectious virus titers in multiple organs, and notably alleviated splenic tissue lesions. After further preclinical evaluations, VV261, identified as a promising candidate drug for the treatment of SFTS, has entered Phase I clinical trials in China, the first such candidate to reach this stage for SFTS.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"41 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885401","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}
Juan Cen, Ping Lu, Chenwei Wang, Jing Wu, Xiaojiao Hu, Han Zhao, Mengyu Li, Mingkai Luo, Shizhen Zhao*, Xiaohui Li* and Shaofeng Duan*,
{"title":"Double Swords in One: Novel Selective PI3K/110β PROTAC Degraders for the Treatment of Multidrug-Resistant Cancer by Activating ERS and Inhibiting P-gp","authors":"Juan Cen, Ping Lu, Chenwei Wang, Jing Wu, Xiaojiao Hu, Han Zhao, Mengyu Li, Mingkai Luo, Shizhen Zhao*, Xiaohui Li* and Shaofeng Duan*, ","doi":"10.1021/acs.jmedchem.4c0316910.1021/acs.jmedchem.4c03169","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03169https://doi.org/10.1021/acs.jmedchem.4c03169","url":null,"abstract":"<p >The p110β isoform of the PI3 kinase (PI3K) family plays a key role in tumorigenesis and PTEN loss-driven multidrug resistance (MDR). Herein, we describe the design, synthesis, and structure–activity relationship studies of a series of small-molecule PI3<i>K</i>/110β PROTACs degraders by combining the selective inhibitor TGX221 of PI3<i>K</i>/110β with VHL ligands. Among them, <b>J-6</b> and <b>J-9</b> exhibited rapid and efficient degradation ability for the target proteins in MDR cells. Meanwhile, the expression and activity of P-glycoprotein were significantly inhibited, leading to a strong synergistic antitumor effect with adriamycin or cisplatin. Further studies confirmed that the two degraders can induce endoplasmic reticulum stress-mediated mitochondrial apoptosis by the AKT/Bcl-2 inhibition-mediated PERK/CHOP-unfolded protein reaction. In vivo studies also verified that the two degraders inhibited the growth of MCF-7/ADM xenograft tumors with high safety. Hence, this study and further optimization of these PI3<i>K</i>/110β PROTAC degraders have broad prospects for the development of new cancer therapies.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 9","pages":"9446–9464 9446–9464"},"PeriodicalIF":6.8,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917155","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}
Yong Cheng, Wei Zheng, Xinru Dong, Tengxiao Sun, Mengwei Xu, Li Xiang, Jian Li, Huilong Wang, Xiaoqin Jian, Jingjin Yu, Pengcheng Li, Tianwen Hu, Guanghui Tian, Xiangrui Jiang, Leike Zhang, Haji A. Aisa*, Yuanchao Xie*, Gengfu Xiao* and Jingshan Shen*,
{"title":"Design and Development of a Novel Oral 4′-Fluorouridine Double Prodrug VV261 against SFTSV","authors":"Yong Cheng, Wei Zheng, Xinru Dong, Tengxiao Sun, Mengwei Xu, Li Xiang, Jian Li, Huilong Wang, Xiaoqin Jian, Jingjin Yu, Pengcheng Li, Tianwen Hu, Guanghui Tian, Xiangrui Jiang, Leike Zhang, Haji A. Aisa*, Yuanchao Xie*, Gengfu Xiao* and Jingshan Shen*, ","doi":"10.1021/acs.jmedchem.5c0062610.1021/acs.jmedchem.5c00626","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00626https://doi.org/10.1021/acs.jmedchem.5c00626","url":null,"abstract":"<p >4′-Fluorouridine (4′-FU), despite demonstrating potent anti-SFTSV efficacy in vitro and in vivo, faces hindrances in its further development as a promising drug due to its weak chemical stability. Here, we report the discovery and development of VV261, a novel 4′-FU double prodrug with three isobutyryl groups on the ribose moiety and a nicotinoyloxymethyl group linked to the imide-nitrogen on the base moiety, exhibiting notable chemical stability and favorable pharmacokinetic properties. In SFTSV-infected mice, VV261 at 5 mg/kg/d for 7 days demonstrated complete protection against lethal SFTSV infection, prevented weight loss, and even a 2 day treatment significantly reduced both viral RNA copies and infectious virus titers in multiple organs, and notably alleviated splenic tissue lesions. After further preclinical evaluations, VV261, identified as a promising candidate drug for the treatment of SFTS, has entered Phase I clinical trials in China, the first such candidate to reach this stage for SFTS.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 9","pages":"9811–9826 9811–9826"},"PeriodicalIF":6.8,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143916974","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}
Marta López-Corrales, Eduardo Izquierdo-García, Manel Bosch, Tapas Das, Amadeu Llebaria, Laia Josa-Culleré, 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, Vicente Marchán","doi":"10.1021/acs.jmedchem.5c00550","DOIUrl":"https://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 <i>N</i>-hexyl COUPY photocages in the mitochondria, which exhibited a remarkable phototoxicity against cancer cells upon green-yellow light irradiation, with IC<sub>50</sub> 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":"7 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880702","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}
Johannes K. Dreizler, Christian Meyners, Wisely Oki Sugiarto, Maximilian L. Repity, Edvaldo V. S. Maciel, Patrick L. Purder, Frederik Lermyte, Stefan Knapp and 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 and Felix Hausch*, ","doi":"10.1021/acs.jmedchem.5c0022010.1021/acs.jmedchem.5c00220","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00220https://doi.org/10.1021/acs.jmedchem.5c00220","url":null,"abstract":"<p >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, BRD4<sup>BD2</sup>, 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-BRD4<sup>BD2</sup> 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.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 9","pages":"9525–9536 9525–9536"},"PeriodicalIF":6.8,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143916975","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}
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, BRD4<sup>BD2</sup>, 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-BRD4<sup>BD2</sup> 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}
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