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Targeting Diacylglycerol Kinase Alpha (DGKα) with New Inhibitors for Enhanced Cancer Immunotherapy 靶向二酰基甘油激酶α (DGKα)的新抑制剂增强癌症免疫治疗
IF 4 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-08-15 DOI: 10.1021/acsmedchemlett.5c00473
Robert B. Kargbo*, 
{"title":"Targeting Diacylglycerol Kinase Alpha (DGKα) with New Inhibitors for Enhanced Cancer Immunotherapy","authors":"Robert B. Kargbo*,&nbsp;","doi":"10.1021/acsmedchemlett.5c00473","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00473","url":null,"abstract":"<p >The development of selective diacylglycerol kinase alpha (DGKα) inhibitors offers a promising strategy to restore T cell activation and enhance antitumor immunity. Combined with immune checkpoint inhibitors (e.g., PD-1, PD-L1), DGKα inhibitors improve immune response and tumor control, representing a potential breakthrough in cancer immunotherapy.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 9","pages":"1724–1726"},"PeriodicalIF":4.0,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Tricyclic and Novel Chemotypes as Selective WRN Helicase Inhibitors for MSI-H Cancer Therapy 三环和新型化学型作为选择性WRN解旋酶抑制剂用于MSI-H癌症治疗
IF 4 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-08-15 DOI: 10.1021/acsmedchemlett.5c00474
Robert B. Kargbo*, 
{"title":"Tricyclic and Novel Chemotypes as Selective WRN Helicase Inhibitors for MSI-H Cancer Therapy","authors":"Robert B. Kargbo*,&nbsp;","doi":"10.1021/acsmedchemlett.5c00474","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00474","url":null,"abstract":"<p >Recent advances targeting WRN helicase highlight a promising synthetic lethality approach for treating microsatellite instability-high (MSI-H) cancers. GlaxoSmithKline and Moma Therapeutics independently developed small molecule inhibitors with distinct chemotypes that disrupt WRN function. Their complementary efforts showcase differentiated selectivity, strategic molecular designs, and a shared focus on exploiting WRN dependency in DNA mismatch repair-deficient tumors.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 9","pages":"1721–1723"},"PeriodicalIF":4.0,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Novel Tricyclic Compounds as ERK5 Inhibitors for Treating Cancer 新型三环化合物作为ERK5抑制剂治疗癌症
IF 4 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-08-15 DOI: 10.1021/acsmedchemlett.5c00478
Ram W. Sabnis*, 
{"title":"Novel Tricyclic Compounds as ERK5 Inhibitors for Treating Cancer","authors":"Ram W. Sabnis*,&nbsp;","doi":"10.1021/acsmedchemlett.5c00478","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00478","url":null,"abstract":"<p >Provided herein are novel tricyclic compounds as ERK5 inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 9","pages":"1727–1728"},"PeriodicalIF":4.0,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
In This Issue, Volume 16, Issue 8 本刊第16卷第8期
IF 4 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-08-14 DOI: 10.1021/acsmedchemlett.5c00429
Andrew P. Riley, 
{"title":"In This Issue, Volume 16, Issue 8","authors":"Andrew P. Riley,&nbsp;","doi":"10.1021/acsmedchemlett.5c00429","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00429","url":null,"abstract":"","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 8","pages":"1435–1436"},"PeriodicalIF":4.0,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144826254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Novel Non-Hallucinogenic Compounds as 5-HT2A Agonists for Treating Mental Health Disorders, Namely Depression, Anxiety, Stress Disorders, and Eating Disorders 新型非致幻化合物作为5-HT2A激动剂治疗精神健康障碍，即抑郁、焦虑、应激障碍和饮食失调
IF 4 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-08-14 DOI: 10.1021/acsmedchemlett.5c00476
Ram W. Sabnis*, 
{"title":"Novel Non-Hallucinogenic Compounds as 5-HT2A Agonists for Treating Mental Health Disorders, Namely Depression, Anxiety, Stress Disorders, and Eating Disorders","authors":"Ram W. Sabnis*,&nbsp;","doi":"10.1021/acsmedchemlett.5c00476","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00476","url":null,"abstract":"<p >Provided herein are novel nonhallucinogenic compounds as 5-HT2A agonists, pharmaceutical compositions, use of such compounds in treating mental health disorders, namely depression, anxiety, stress disorders and eating disorders, and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 9","pages":"1717–1718"},"PeriodicalIF":4.0,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Novel Fused Heterocycles as 5-HT2A Receptor Agonists for Treating Neurological Diseases, Namely, Depression, Anxiety, Substance Abuse, and Headaches 新型融合杂环化合物作为5-HT2A受体激动剂治疗神经系统疾病，即抑郁、焦虑、药物滥用和头痛
IF 4 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-08-13 DOI: 10.1021/acsmedchemlett.5c00477
Ram W. Sabnis*, 
{"title":"Novel Fused Heterocycles as 5-HT2A Receptor Agonists for Treating Neurological Diseases, Namely, Depression, Anxiety, Substance Abuse, and Headaches","authors":"Ram W. Sabnis*,&nbsp;","doi":"10.1021/acsmedchemlett.5c00477","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00477","url":null,"abstract":"<p >Provided herein are novel fused heterocycles as 5-HT2A receptor agonists, pharmaceutical compositions, use of such compounds in treating neurological diseases, namely depression, anxiety, substance abuse and headaches, and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 9","pages":"1715–1716"},"PeriodicalIF":4.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
A Nucleoside Analogue Featuring a C3′-Stereogenic All-Carbon Quaternary Center as a Bioenergetic Disruptor of KRAS-Mutated Pancreatic Cancer Cells 一种核苷类似物，具有C3 ' -立体全碳四元中心作为kras突变胰腺癌细胞的生物能量干扰物
IF 4 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-08-12 DOI: 10.1021/acsmedchemlett.5c00378
Houda Tantawi, Philippe Mochirian, Mathieu Truong, Janie Beauregard, Laura Collins, Georges Kanaan, Hiba Komati, Louis Leblanc, Wael Maharsy, Amarender Manchoju, Ryan Simard, Guillaume Tambutet, Claudia Teran, Starr Dostie, Michel Prévost, Mona Nemer* and Yvan Guindon*, 
{"title":"A Nucleoside Analogue Featuring a C3′-Stereogenic All-Carbon Quaternary Center as a Bioenergetic Disruptor of KRAS-Mutated Pancreatic Cancer Cells","authors":"Houda Tantawi,&nbsp;Philippe Mochirian,&nbsp;Mathieu Truong,&nbsp;Janie Beauregard,&nbsp;Laura Collins,&nbsp;Georges Kanaan,&nbsp;Hiba Komati,&nbsp;Louis Leblanc,&nbsp;Wael Maharsy,&nbsp;Amarender Manchoju,&nbsp;Ryan Simard,&nbsp;Guillaume Tambutet,&nbsp;Claudia Teran,&nbsp;Starr Dostie,&nbsp;Michel Prévost,&nbsp;Mona Nemer* and Yvan Guindon*,&nbsp;","doi":"10.1021/acsmedchemlett.5c00378","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00378","url":null,"abstract":"<p >A novel nucleoside analogue, LCB-2151, has been developed to induce cell death in <i>KRAS</i>-mutated pancreatic human cancer cell lines, which exhibit partial resistance to gemcitabine, a widely used anticancer drug. LCB-2151 disrupts the two primary sources of ATP production, namely, glycolysis and mitochondrial oxidative phosphorylation, reducing the bioenergetic capacity of these cells and inducing the formation of reactive oxygen species. Metabolomics and mitochondrial respiration analyses reveal that LCB-2151 inhibits key enzymes in glycolysis, the TCA cycle, and fatty acid β-oxidation. These findings highlight a coordinated mechanism driving bioenergetic disruption and cell death.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 9","pages":"1814–1824"},"PeriodicalIF":4.0,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Synthesis and Antiviral Evaluation of Unexplored Dioxolane-Derived 7-Deazapurine Nucleoside Analogues against Epstein–Barr Virus (EBV) 未开发的二氧唑烷衍生的7-去氮杂嘌呤核苷类似物的合成及对eb病毒的抗病毒作用评价
IF 4 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-08-12 DOI: 10.1021/acsmedchemlett.5c00397
Uma S. Singh*, Ransom A. Jones, Yugandhar Kothapalli, Shuiyun Lan, Xing-Quan Zhang, Ryan L. Slack, Harischandra P. Thoomu, Robert T. Schooley, Stefan G. Sarafianos and Chung K. Chu, 
{"title":"Synthesis and Antiviral Evaluation of Unexplored Dioxolane-Derived 7-Deazapurine Nucleoside Analogues against Epstein–Barr Virus (EBV)","authors":"Uma S. Singh*,&nbsp;Ransom A. Jones,&nbsp;Yugandhar Kothapalli,&nbsp;Shuiyun Lan,&nbsp;Xing-Quan Zhang,&nbsp;Ryan L. Slack,&nbsp;Harischandra P. Thoomu,&nbsp;Robert T. Schooley,&nbsp;Stefan G. Sarafianos and Chung K. Chu,&nbsp;","doi":"10.1021/acsmedchemlett.5c00397","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00397","url":null,"abstract":"<p >Dioxolane-based nucleosides are characterized by their unique replacement of the sugar moiety by dioxolane-based cyclopentyl rings. A series of <span>d</span>-dioxolane-derived 7-deazapurine analogues (<b>12</b>–<b>19</b>) were synthesized and evaluated against Epstein–Barr virus (EBV) and human immunodeficiency virus (HIV). The 7-bromo-deazaadenosine analogue (<b>15</b>) demonstrated an EC<sub>50</sub> of 0.17 μM and the 7-iodo-deazaadeosine analogue (<b>16</b>) displayed an EC<sub>50</sub> of 0.47 μM, compared to ganciclovir (EC<sub>50</sub> = 2.5 μM) against EBV. Compound <b>15</b> was 14 times more potent than ganciclovir, with a high selectivity index (SI = 294). Additionally, the deazaadenosine analogue (<b>12</b>) and 7-fluoro-deazaadenosine (<b>13</b>) have shown moderate antiviral potency against HIV. The reported analogues of this series expressed both potency and selectivity against EBV. The development of prodrugs for analogues <b>12</b>, <b>13</b>, <b>15</b>, and <b>16</b> may potentially enhance their antiviral activity against EBV and HIV, offering a promising avenue for identifying preclinical candidates effective against both DNA and RNA viruses.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 9","pages":"1844–1851"},"PeriodicalIF":4.0,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.5c00397","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Terpene-Based Thiazole Hydrazines as Negative Allosteric Modulators of MRGPRX4: In Vitro Evaluation and Binding Site Analysis 萜烯基噻唑肼作为MRGPRX4的负变构调节剂：体外评价和结合位点分析
IF 4 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-08-10 DOI: 10.1021/acsmedchemlett.5c00354
Saqlain Haider, Manal M. Alhusban, Pankaj Pandey, Suresh Chandra V. A. R. Annam, Robert B. Laprairie and Amar G. Chittiboyina*, 
{"title":"Terpene-Based Thiazole Hydrazines as Negative Allosteric Modulators of MRGPRX4: In Vitro Evaluation and Binding Site Analysis","authors":"Saqlain Haider,&nbsp;Manal M. Alhusban,&nbsp;Pankaj Pandey,&nbsp;Suresh Chandra V. A. R. Annam,&nbsp;Robert B. Laprairie and Amar G. Chittiboyina*,&nbsp;","doi":"10.1021/acsmedchemlett.5c00354","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00354","url":null,"abstract":"<p >The human MAS-related G-protein-coupled receptors (MRGPRs) represent a promising therapeutic target for managing chronic itch and pain. Among them, MRGPRX4 is activated by bile acids in dorsal root ganglia (DRG) neurons and contributes to the cholestatic itch. Here, we report the design, synthesis, and in vitro evaluation of a focused library of functionalized terpene-based thiazole hydrazines targeting MRGPRX receptors. Functional assays identified two compounds, <b>1C</b> and <b>3G</b>, as negative allosteric modulators (NAMs) of MRGPRX4 with IC<sub>50</sub> values of 337 nM and 15.5 μM, respectively, and showed weak activity at MRGPRX2. Computational analysis suggested a putative NAM binding site adjacent to the orthosteric pocket involving key interactions with residues H92<sup>3.22</sup>, K96<sup>3.26</sup>, and R159<sup>4.62</sup>. The resulting site overlaps with the receptor activity-modifying protein 2 (RAMP2) interaction region, where RAMP2 antagonizes MRGPRX4 as a NAM. These findings provide a foundation for developing selective MRGPRX4 NAMs as novel therapeutic agents for chronic itch and pain.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 9","pages":"1798–1805"},"PeriodicalIF":4.0,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Novel Compounds as 5-HT2A Agonists for Treating Mental Illness or CNS Disorders 新化合物作为5-HT2A激动剂治疗精神疾病或中枢神经系统疾病
IF 4 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-08-08 DOI: 10.1021/acsmedchemlett.5c00460
Ram W. Sabnis*, 
{"title":"Novel Compounds as 5-HT2A Agonists for Treating Mental Illness or CNS Disorders","authors":"Ram W. Sabnis*,&nbsp;","doi":"10.1021/acsmedchemlett.5c00460","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00460","url":null,"abstract":"<p >Provided herein are novel compounds as 5-HT2A agonists, pharmaceutical compositions, use of such compounds in treating mental illness or CNS disorders, and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 9","pages":"1711–1712"},"PeriodicalIF":4.0,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
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