Journal of Medicinal Chemistry最新文献

{"title":"Structural Optimization of Pyrazole Compounds as Hsp90 Regulators with Enhanced Antitumor Activity","authors":"Zi-Wen Feng, Li Li, Shi-Duo Zhang, Ying-Ji Wang, Jia-Yue Pei, Nan-Nan Chen, Bei-Duo Wu, Qiu-Ling Zheng, Qi-Dong You, Xiao-Ke Guo, Xiao-Li Xu","doi":"10.1021/acs.jmedchem.4c02182","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02182","url":null,"abstract":"Targeting Hsp90 is an effective strategy for cancer therapy. TAS-116 has been approved for the treatment of gastrointestinal stromal tumors. Our previous studies identified a series of pyrazole derivatives as covalent Hsp90 inhibitors that allosterically disrupt the Hsp90-Cdc37 interaction. Here, through systematic structure–activity relationship (SAR) optimization, compound <b>39</b> (<b>DDO-6691</b>) with a new covalent warhead was developed, which demonstrates improved ADME properties and significantly enhanced antitumor activity. Notably, parental HCT-116 cells exhibited markedly greater sensitivity to compound <b>39</b> (IC₅₀ &gt; 50 μM) compared to their Cdc37-knockout counterparts. Importantly, compound <b>39</b> displayed potent tumor growth inhibition in HCT-116 xenograft mouse models. These collective findings underscore the therapeutic promise of covalent Hsp90-targeted disruption of the Hsp90-Cdc37 complex, offering a novel mechanistic approach to cancer treatment.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"56 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143898181","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":"Bardoxolone Derivatives as Novel Pseudo-Natural Necroptosis Inhibitors by Destabilizing HSP90 Client Proteins","authors":"Yu Zou, Yue Chai, Bolin Du, Yufeng Xin, Linjing Zhao, Runhui Liu, Weidong Zhang, Chunlin Zhuang","doi":"10.1021/acs.jmedchem.4c02336","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02336","url":null,"abstract":"Targeting necroptosis has been confirmed as an efficient treatment strategy for inflammatory diseases. 2-Cyano-3,12-dioxo-olean-1,9-diene-28-carboxylic acid (CDDO) was previously identified as a pseudonatural-product necroptosis inhibitor. However, CDDO was inactive in murine cells and less active in human cells. In this study, 27 derivatives of CDDO were synthesized by structural modification in A and D/E rings, among which <b>ZYH-23</b> had the best activity. It could effectively block necroptosis in both human and murine cells and soon alleviate SIRS-induced hypothermia and death by remarkably decreasing proinflammatory factors <i>in vivo</i>. For the mechanism, <b>ZYH-23</b> blocked necroptosis by targeting HSP90 to inhibit the phosphorylation of RIPK1, RIPK3, and MLKL. Notably, different from that of CDDO, <b>ZYH-23</b> could induce destabilizing HSP90 client proteins in a short-term treatment and in a proteasome- and lysosome-independent manner. In summary, the present study provided a series of novel pseudonatural inhibitory candidates for necroptosis-related diseases with a new mechanism.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"90 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893984","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":"Celebrating the Drug Annotation Series and the Importance of Publishing","authors":"Wendy B. Young","doi":"10.1021/acs.jmedchem.5c01064","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01064","url":null,"abstract":"As I conclude my fifth year as Associate Editor of the &lt;i&gt;Drug Annotation Series&lt;/i&gt; for the &lt;i&gt;Journal of Medicinal Chemistry&lt;/i&gt;, I remain deeply inspired by the remarkable work we do as medicinal chemists and drug hunters. The profound positive impact we have on society is a testament to our collective expertise, creativity, and relentless dedication to developing the best medicines possible. This Special Collection celebrates the Drug Annotation Series recognizing the invaluable contributions of medicinal chemists and drug discovery scientists around the globe. As you immerse yourself in this Special Collection, absorbing the science shared and gaining insights from others, I invite you to also reflect on your personal choices regarding what, when, and how to publish your scientific findings and accomplishments. Publishing research findings serves many important purposes, but one of the most impactful is accelerating scientific progress. Drug discovery is not the work of a lone scientist tinkering in a lab─it requires the collaboration of dedicated teams, from researchers and developers to clinical trial participants. By sharing discoveries, we enable scientists to build on each other’s work, refine theories, and avoid repeating ineffective approaches. This leads to faster innovation, which is crucial because patients are waiting─and counting on us. Writing is learning. Often it is not until you put pen to paper, that you realize gaps in logic, a missing reference, or critical connections. It pushes you to think deeper as you expose yourself to reviewers and readers. Managers have a responsibility to mentor their employees in crafting compelling manuscripts. Allocating dedicated time for this task is essential, ensuring it becomes part of annual goals and work hours, rather than being relegated to evenings and weekends, where it may be overlooked amid the challenges of work–life balance. In the pharmaceutical industry, competition to develop the best and first-in-class agents is intense, putting sharing at odds with competitive advantage. Company cultures around publication practices vary significantly. Some organizations take risks, sharing key advancements early to establish scientific leadership and claim high-impact contributions to the field. Others adopt a cautious approach, waiting longer to protect vital findings and discoveries, particularly Structure–Activity Relationship (SAR) insights, which are crucial for advancing best-in-class compounds. Of course, patents must be considered. Balancing the protection of intellectual property with the need to share groundbreaking discoveries is essential to driving innovation. All countries require an invention to be novel, so public disclosure can prevent you from obtaining a patent. In the U.S., there is a one-year grace period, but many countries require absolute novelty, meaning any public disclosure can jeopardize patentability. Thus, filing before publishing ensures preservation of intern","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"24 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143890292","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":"Inverse Agonists of Peroxisome Proliferator-Activated Receptor Gamma: Advances and Prospects in Cancer Treatment","authors":"Wensong Deng,&nbsp;Xuejian Wang,&nbsp;Xinyu Niu,&nbsp;Xiangjie Zhang,&nbsp;Yunlei Hou* and Mingze Qin*,&nbsp;","doi":"10.1021/acs.jmedchem.5c0067310.1021/acs.jmedchem.5c00673","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00673https://doi.org/10.1021/acs.jmedchem.5c00673","url":null,"abstract":"<p >Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent nuclear transcription factor that modulates metabolic homeostasis and cell proliferation. Inverse agonism of PPARγ is an emerging anticancer strategy, particularly for the treatment of bladder cancer. The first-in-class PPARγ inverse agonist, FX-909, is currently being studied in clinical trials for cancer treatment. However, PPARγ inverse agonists are still in the early stages of development. The discovery of compounds with novel chemical structures, potent efficacy, and favorable pharmacokinetic properties is urgently needed. In this perspective, the biological functions of PPARγ and its role in cancer pathology are introduced, and currently available PPARγ inverse agonists and their preliminary structure–activity relationships (SARs) are discussed from a medicinal chemistry viewpoint. These findings inform the development of anticancer agents that act as PPARγ inverse agonists. Furthermore, our discussion of the complex biological functions of PPARγ provides insights into the exploration of its role in various diseases.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 9","pages":"9084–9100 9084–9100"},"PeriodicalIF":6.8,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917225","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, 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, Song Li","doi":"10.1021/acs.jmedchem.4c03131","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c03131","url":null,"abstract":"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 (EC₅₀ = 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.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"222 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of ATX968: An Orally Available Allosteric Inhibitor of DHX9","authors":"Matthew H. Daniels, Jennifer Castro, Young-Tae Lee, Deepali Gotur, Kevin E. Knockenhauer, Simina Grigoriu, Gordon J. Lockbaum, Jae Eun Cheong, Chuang Lu, David Brennan, Shane M. Buker, Julie Liu, Shihua Yao, Brian A. Sparling, E. Allen Sickmier, Scott Ribich, Steve J. Blakemore, Serena J. Silver, P. Ann Boriack-Sjodin, Kenneth W. Duncan, Robert A. Copeland","doi":"10.1021/acs.jmedchem.5c00252","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00252","url":null,"abstract":"DHX9 is an RNA/DNA helicase integral in the maintenance of genome stability that has emerged as an attractive target for oncology drug discovery. Disclosed herein is the discovery and optimization of a series of DHX9 inhibitors. Compound <b>1</b> was identified as a partial inhibitor of DHX9 ATPase activity but a full inhibitor of unwinding activity. Binding of <b>1</b> to a pocket distinct from the ATP binding site was confirmed by X-ray crystallography, enabling structure-based drug optimization. During this optimization, a sulfur–halogen bond was identified that increased on-target residence time without impacting equilibrium binding affinity. Analysis shows that cell potency more closely correlates with residence time than with equilibrium measurements of binding affinity or biochemical potency. Further optimization of potency and ADME properties led to the identification of <b>ATX968</b>, a potent and selective DHX9 inhibitor that is efficacious in a tumor xenograft model of microsatellite instability-high (MSI-H) colorectal cancer.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"81 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885399","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":"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, Julian C. Lo","doi":"10.1021/acs.jmedchem.5c00596","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00596","url":null,"abstract":"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.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"91 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143890293","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":"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, Lin-Kun An","doi":"10.1021/acs.jmedchem.4c02951","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02951","url":null,"abstract":"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> (IC₅₀ = 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.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"140 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885397","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":"Inverse Agonists of Peroxisome Proliferator-Activated Receptor Gamma: Advances and Prospects in Cancer Treatment","authors":"Wensong Deng, Xuejian Wang, Xinyu Niu, Xiangjie Zhang, Yunlei Hou, Mingze Qin","doi":"10.1021/acs.jmedchem.5c00673","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00673","url":null,"abstract":"Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent nuclear transcription factor that modulates metabolic homeostasis and cell proliferation. Inverse agonism of PPARγ is an emerging anticancer strategy, particularly for the treatment of bladder cancer. The first-in-class PPARγ inverse agonist, FX-909, is currently being studied in clinical trials for cancer treatment. However, PPARγ inverse agonists are still in the early stages of development. The discovery of compounds with novel chemical structures, potent efficacy, and favorable pharmacokinetic properties is urgently needed. In this perspective, the biological functions of PPARγ and its role in cancer pathology are introduced, and currently available PPARγ inverse agonists and their preliminary structure–activity relationships (SARs) are discussed from a medicinal chemistry viewpoint. These findings inform the development of anticancer agents that act as PPARγ inverse agonists. Furthermore, our discussion of the complex biological functions of PPARγ provides insights into the exploration of its role in various diseases.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"35 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143890295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of ATX968: An Orally Available Allosteric Inhibitor of DHX9","authors":"Matthew H. Daniels,&nbsp;Jennifer Castro,&nbsp;Young-Tae Lee,&nbsp;Deepali Gotur,&nbsp;Kevin E. Knockenhauer,&nbsp;Simina Grigoriu,&nbsp;Gordon J. Lockbaum,&nbsp;Jae Eun Cheong,&nbsp;Chuang Lu,&nbsp;David Brennan,&nbsp;Shane M. Buker,&nbsp;Julie Liu,&nbsp;Shihua Yao,&nbsp;Brian A. Sparling*,&nbsp;E. Allen Sickmier,&nbsp;Scott Ribich,&nbsp;Steve J. Blakemore,&nbsp;Serena J. Silver,&nbsp;P. Ann Boriack-Sjodin,&nbsp;Kenneth W. Duncan and Robert A. Copeland,&nbsp;","doi":"10.1021/acs.jmedchem.5c0025210.1021/acs.jmedchem.5c00252","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c00252https://doi.org/10.1021/acs.jmedchem.5c00252","url":null,"abstract":"<p >DHX9 is an RNA/DNA helicase integral in the maintenance of genome stability that has emerged as an attractive target for oncology drug discovery. Disclosed herein is the discovery and optimization of a series of DHX9 inhibitors. Compound <b>1</b> was identified as a partial inhibitor of DHX9 ATPase activity but a full inhibitor of unwinding activity. Binding of <b>1</b> to a pocket distinct from the ATP binding site was confirmed by X-ray crystallography, enabling structure-based drug optimization. During this optimization, a sulfur–halogen bond was identified that increased on-target residence time without impacting equilibrium binding affinity. Analysis shows that cell potency more closely correlates with residence time than with equilibrium measurements of binding affinity or biochemical potency. Further optimization of potency and ADME properties led to the identification of <b>ATX968</b>, a potent and selective DHX9 inhibitor that is efficacious in a tumor xenograft model of microsatellite instability-high (MSI-H) colorectal cancer.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 9","pages":"9537–9554 9537–9554"},"PeriodicalIF":6.8,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.jmedchem.5c00252","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917189","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}