{"title":"The Great Potential of the Cluster of Differentiation 38 (CD38) Inhibitors in the Treatment of Cancer and Age-Related Metabolic dysfunction","authors":"Ahmed F. Abdel-Magid*, ","doi":"10.1021/acsmedchemlett.6c00266","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00266","url":null,"abstract":"<p >The invention in this patent application relates to heterobicyclic amide derivatives represented herein generally by formula 1. These compounds are inhibitors of CD38 and may be useful in the treatment of cancer and other diseases.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 7","pages":"1458–1461"},"PeriodicalIF":3.9,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409293","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}
{"title":"High-Throughput CETSA Identifies Small Molecule Modulators of ILT3 (LILRB4) with Functional Activity in Human iPSC-Derived Microglia for Alzheimer’s Disease","authors":"Somaya A. Abdel-Rahman, and , Moustafa Gabr*, ","doi":"10.1021/acsmedchemlett.6c00244","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00244","url":null,"abstract":"<p >Immune inhibitory signaling in microglia contributes to impaired amyloid-β (Aβ) clearance and neuroinflammation in Alzheimer’s disease (AD), yet small molecule modulators targeting these pathways remain largely unexplored. Here, we report the development of a high-throughput cellular thermal shift assay (HT-CETSA) platform for identification of small molecule binders targeting the inhibitory immune receptor ILT3 (LILRB4). Screening of ∼40 000 compounds yielded multiple validated hits, including <b>IB15C</b>, a submicromolar ILT3 binder identified through preliminary structure–activity relationship optimization. Orthogonal validation by microscale thermophoresis, surface plasmon resonance, docking, and site-directed mutagenesis confirmed direct and target-specific ILT3 engagement. Functionally, <b>IB15C</b> disrupted the ILT3-ApoE interaction and restored microglial activity in human iPSC-derived microglia, reducing SHP1/2 and NF-κB signaling, suppressing IL-1β secretion, and enhancing Aβ uptake. <b>IB15C</b> also demonstrated favorable in vitro pharmacokinetic and safety properties, supporting further development of ILT3-targeted neuroimmune therapeutics.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 7","pages":"1647–1654"},"PeriodicalIF":3.9,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409282","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}
Yaopeng Zhao, Jingmin Cui, Hui Wen, Xiaoyue Dai, Liangsheng Jiang and Ye Fang*,
{"title":"Probe and Assay Dependent Pharmacology of Dantrolene Analogues at the GPR35","authors":"Yaopeng Zhao, Jingmin Cui, Hui Wen, Xiaoyue Dai, Liangsheng Jiang and Ye Fang*, ","doi":"10.1021/acsmedchemlett.6c00056","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00056","url":null,"abstract":"<p >The G-protein-coupled receptor 35 (GPR35) plays a key role in various physiological and pathological processes and has emerged as a potential therapeutic target for the treatment of pain, inflammation, and metabolic diseases. Herein, we report the discovery and characterization of dantrolene analogues as GPR35 ligands. Pharmacological profiling with label-free dynamic mass redistribution and Tango arrestin assays showed that the 2,4-imidazolidinedione-containing analogues of dantrolene act as partial agonists of the GPR35, while its urea, thiourea, or amido derivatives display probe and assay dependent antagonism against the receptor.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 7","pages":"1524–1530"},"PeriodicalIF":3.9,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409362","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}
{"title":"Novel Compounds for Inhibiting Viral Replication and Treating and/or Preventing Coronavirus Infections","authors":"Ram W. Sabnis*, ","doi":"10.1021/acsmedchemlett.6c00315","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00315","url":null,"abstract":"<p >Provided herein are novel compounds, pharmaceutical compositions, use of such compounds in inhibiting viral replication and treating and/or preventing coronavirus infections, and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 7","pages":"1487–1489"},"PeriodicalIF":3.9,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409330","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}
{"title":"Novel 5,6-Bicyclic Compounds as 5-HT2A Receptor Agonists for Treating Depression, Anxiety, Substance Abuse, and Headaches","authors":"Ram W. Sabnis*, and , Anika R. Sabnis, ","doi":"10.1021/acsmedchemlett.6c00270","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00270","url":null,"abstract":"<p >Provided herein are novel 5,6-bicyclic compounds as 5-HT2A receptor agonists, pharmaceutical compositions, use of such compounds in treating depression, anxiety, substance abuse and headaches, and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 7","pages":"1451–1452"},"PeriodicalIF":3.9,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409397","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}
{"title":"Development of Selective PARP1 Inhibitors for the Treatment of Cancer","authors":"Xin Zhou, and , Steven H. Liang*, ","doi":"10.1021/acsmedchemlett.6c00296","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00296","url":null,"abstract":"<p >PARP1 is a key DNA damage response enzyme that supports tumor-cell survival through PARP-mediated DNA repair. Although FDA-approved PARP inhibitors have validated this therapeutic strategy, limited PARP1/PARP2 selectivity may cause adverse effects. This patent discloses next-generation PARP1 inhibitors with improved potency, selectivity, and brain-penetrant pharmacokinetic properties.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 7","pages":"1480–1482"},"PeriodicalIF":3.9,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409461","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}
{"title":"Novel Indolinyl Compounds as Helicase Primase Inhibitors for Treating Viral Infections, in particular, Herpesvirus Infections","authors":"Ram W. Sabnis*, ","doi":"10.1021/acsmedchemlett.6c00288","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00288","url":null,"abstract":"<p >Provided herein are novel indolinyl compounds as helicase primase inhibitors, pharmaceutical compositions, use of such compounds in treating viral infections, in particular, herpesvirus infections, and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 7","pages":"1466–1467"},"PeriodicalIF":3.9,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409337","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}
{"title":"Novel Substituted Heterocyclic Carboxamindes as α2C-ARs Antagonists","authors":"Jian Rong, and , Steven H. Liang*, ","doi":"10.1021/acsmedchemlett.6c00295","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00295","url":null,"abstract":"<p >This patent describes heterocyclic carboxamindes as new, highly effective α2C-Adrenergic receptor (α2C-AR) antagonists, suitable for treating α2C-ARs-associated disorders. It offers detailed information on the heterocyclic carboxamindes, pharmaceutical formulations, and their applications in managing α2C-ARs-related conditions.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 7","pages":"1477–1479"},"PeriodicalIF":3.9,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409256","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}
Di Zhao, Wengang Wang, Zhichang Xu, Zewei Mao, Ruirui Wang, Huan Chen* and Chunyan Hu*,
{"title":"Vasicine-Based Synergistic Antifungal Agents against FLC-Resistant Candida albicans Targeting Ras/cAMP/PKA Pathway","authors":"Di Zhao, Wengang Wang, Zhichang Xu, Zewei Mao, Ruirui Wang, Huan Chen* and Chunyan Hu*, ","doi":"10.1021/acsmedchemlett.6c00192","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.6c00192","url":null,"abstract":"<p >A series of novel vasicine-based derivatives were designed and synthesized, and in vitro antifungal activities were evaluated. Most compounds showed synergistic antifungal effects with fluconazole (FLC) against FLC-resistant <i>C. albicans</i>. Compound <b>3n</b> exhibited the best activity (MIC<sub>50</sub> = 1.29 μM, FICI = 0.01) with no obvious cytotoxicity to 16HBE cells. Mechanistic studies revealed that <b>3n</b> combined with FLC inhibited biofilm formation and efflux pump activity, and synergistically targeted the Ras/cAMP/PKA pathway to block yeast-to-hyphae transition. This dual mechanism provides a new strategy for treating FLC-resistant <i>C. albicans</i> infections.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 7","pages":"1621–1628"},"PeriodicalIF":3.9,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409327","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}
Timothy Henderson*, Michael D. Altman, Alexei V. Buevich, Brandon Cash, Saso Cemerski, Wonsuk Chang, Yiping Chen, Matthew Childers, Jared Cumming, Peter J. Dandliker, Guo Feng, Andrew Haidle, Robert P. Hayes, Thu Ho, James P. Jewell, Ilona Kariv, Ian Knemeyer, Johnny Kopinja, Brian M. Lacey, Jason Laskey, Charles A. Lesburg, Rui Liang, Jongwon Lim, Brian J. Long, Min Lu, Yanhong Ma, Ellen C. Minnihan, Ryan D. Otte, Gregory O’Donnell, Bo-Sheng Pan, Samanthi A. Perera, Jennifer A. Piesvaux, Jeremy P. Presland, Laura Price, Larissa Rakhilina, Berengere Sauvagnat, Gottfried K. Schroeder, Sharad Sharma, B. Wesley Trotter, Sriram Tyagarajan, Hyun Woo, Daniel F. Wyss, Serena Xu, George H. Addona and David Jonathan Bennett,
{"title":"Discovery of MK-2118, a Small-Molecule Agonist of STING","authors":"Timothy Henderson*, Michael D. Altman, Alexei V. Buevich, Brandon Cash, Saso Cemerski, Wonsuk Chang, Yiping Chen, Matthew Childers, Jared Cumming, Peter J. Dandliker, Guo Feng, Andrew Haidle, Robert P. Hayes, Thu Ho, James P. Jewell, Ilona Kariv, Ian Knemeyer, Johnny Kopinja, Brian M. Lacey, Jason Laskey, Charles A. Lesburg, Rui Liang, Jongwon Lim, Brian J. Long, Min Lu, Yanhong Ma, Ellen C. Minnihan, Ryan D. Otte, Gregory O’Donnell, Bo-Sheng Pan, Samanthi A. Perera, Jennifer A. Piesvaux, Jeremy P. Presland, Laura Price, Larissa Rakhilina, Berengere Sauvagnat, Gottfried K. Schroeder, Sharad Sharma, B. Wesley Trotter, Sriram Tyagarajan, Hyun Woo, Daniel F. Wyss, Serena Xu, George H. Addona and David Jonathan Bennett, ","doi":"10.1021/acsmedchemlett.5c00540","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00540","url":null,"abstract":"<p >Agonists of Stimulator of Interferon Genes (STING) have the potential to activate the innate and adaptive immune system for cancer treatment. Early efforts in identifying suitable therapeutics were focused on cyclic dinucleotide (CDN) analogs of 2′,3′-cGAMP, the endogenous ligand to STING. CDNs lack of tractable bioavailability led us to consider small-molecule modulators of STING. We previously reported the identification of MSA-2, an orally available non-nucleotide STING agonist with antitumor activity. Optimization efforts in this series faced challenges with uniform activity across species, cell shift, and steep structure activity relationships. Herein we report lead optimization efforts guided by structure-based drug design to identify the MSA-2 analog MK-2118.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"17 7","pages":"1501–1507"},"PeriodicalIF":3.9,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409352","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}
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