Bioorganic & Medicinal Chemistry Letters最新文献

1,2,3-Triazole‑gold(I)-triethylphosphine derivatives of nutrients as new antimicrobials against antibiotic resistant Gram-positive pathogens. 1,2,3-三唑金(I)-三乙基膦营养物衍生物作为抗革兰氏阳性耐药病原体的新抗生素。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-14 DOI: 10.1016/j.bmcl.2025.130276

Mathieu Michaut, Françoise Hoegy, Alexandre Steffen, Jean-Marie Contreras, Christophe Morice, Patrick Plésiat, Gaëtan L A Mislin

引用次数: 0

The discrepancies in amino acid sequence of the phosphate-binding loop lead to distinctive binding modes of a covalent inhibitor for MAP2K1 and MAP2K6: Structural insights for producing selective inhibitors 磷酸结合环氨基酸序列的差异导致MAP2K1和MAP2K6共价抑制剂的不同结合模式：生产选择性抑制剂的结构见解

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-14 DOI: 10.1016/j.bmcl.2025.130277

Seigo Yumura , Kei Moritsugu , Daisuke Kitagawa , Masaaki Sawa , Takayoshi Kinoshita

{"title":"The discrepancies in amino acid sequence of the phosphate-binding loop lead to distinctive binding modes of a covalent inhibitor for MAP2K1 and MAP2K6: Structural insights for producing selective inhibitors","authors":"Seigo Yumura , Kei Moritsugu , Daisuke Kitagawa , Masaaki Sawa , Takayoshi Kinoshita","doi":"10.1016/j.bmcl.2025.130277","DOIUrl":"10.1016/j.bmcl.2025.130277","url":null,"abstract":"<div><div>Mitogen-activated protein kinase kinase 6 (MAP2K6) plays a crucial role in activating the p38 MAPK pathway, and dysregulation of this pathway is associated with serious diseases including autoimmune diseases. 5Z-7-oxozeaenol (5Z7O), a covalent-binding inhibitor, inhibits MAP2K6 approximately ten times more strongly than MAP2K1, a common off-target kinase of MAP2K6. Here, we determined the crystal structure of the 5Z7O-MAP2K6 complex and carefully compared it with that of the 5Z7O-MAP2K1 complex previously reported. The binding orientation of 5Z7O is slightly different between the MAP2K1 and MAP2K6 complexes, resulting in different hydrogen-bond networks and thereby the higher potency of 5Z7O for MAP2K6 than MAP2K1. 5Z7O formed hydrogen bonds with the arginine residue in the catalytic HRD motif of MAP2K6 and asparagine residue in the solvent-accessible region but not with the corresponding residues of MAP2K1. Structural comparison implied that these differences in hydrogen bonding were attributable to differences in the phosphate-binding loop (P-loop) between MAP2K6 and MAP2K1. Molecular dynamics simulation revealed the above-mentioned and further structural features of MAP2K1 and MAP2K6. These distinct structural features are potentially useful for producing selective inhibitors for MAP2K1 and MAP2K6.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"125 ","pages":"Article 130277"},"PeriodicalIF":2.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144072167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 DC20 as a potential non-nucleoside reverse transcriptase inhibitor with excellent pharmacokinetic properties 发现DC20作为一种潜在的非核苷类逆转录酶抑制剂，具有良好的药代动力学特性。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-13 DOI: 10.1016/j.bmcl.2025.130267

Jia-Yu Liu , Meng-Di Ma , Yi-Ming Li , Cong-Qiang Xie , Jia-Rui Wu , Kai-Ting Yan , Deng-Yu Niu , Rong-Hua Luo , Yue-Ping Wang , Yong-Tang Zheng , Zhen-nan She , Hong-Bing Zhang , Liu-Meng Yang , Yan-Ping He

{"title":"Discovery of DC20 as a potential non-nucleoside reverse transcriptase inhibitor with excellent pharmacokinetic properties","authors":"Jia-Yu Liu , Meng-Di Ma , Yi-Ming Li , Cong-Qiang Xie , Jia-Rui Wu , Kai-Ting Yan , Deng-Yu Niu , Rong-Hua Luo , Yue-Ping Wang , Yong-Tang Zheng , Zhen-nan She , Hong-Bing Zhang , Liu-Meng Yang , Yan-Ping He","doi":"10.1016/j.bmcl.2025.130267","DOIUrl":"10.1016/j.bmcl.2025.130267","url":null,"abstract":"<div><div><em>S</em>-DACOs are a series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) known for their effective antiviral activity and low cytotoxicity, although their water solubility and bioavailability have been suboptimal. In this study, we synthesized and evaluated 25 novel compounds, most of which demonstrated a CLogP below 5 and exhibited potent antiviral activity against HIV-1<sub>IIIB</sub> with EC<sub>50</sub> values ranging from 0.86 to 0.004 μmol/L. Among them, compound <strong>DC20</strong> (EC<sub>50</sub> = 0.004 μM, CC<sub>50</sub> = 134.21 ± 0.78 μM, SI = 33,552) emerged as particularly promising, it effectively targets reverse transcriptase and maintains high efficacy against mutant strains V106M, K103N, and Y181C. Particularly notable is that <strong>DC20</strong> possesses excellent pharmacokinetic properties, with an oral bioavailability reaching up to 89.1 %. Given its high potency and low toxicity, <strong>DC20</strong> holds significant potential for drug development and may serve as a critical candidate for future clinical applications. Further investigations will focus on its pharmaceutical viability.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"125 ","pages":"Article 130267"},"PeriodicalIF":2.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Design, synthesis and anti-GBM activities of amide-modified Curcumol derivatives 酰胺修饰莪术酚衍生物的设计、合成及抗gbm活性研究。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-06 DOI: 10.1016/j.bmcl.2025.130265

Shiqi Hu , Yuhang Fan , Yumo Zhao, Zhengyang Gao, Jie Lu, Jian Li, Jinlian Wei, Yongqiang Zhang

引用次数: 0

Overcoming CK1α liability in the discovery of a series of isoIndolinone Glutarimides as selective IKZF2 molecular glue degraders 克服CK1α倾向性，发现一系列异吲哚酮戊二酰亚胺作为选择性IKZF2分子胶降解剂

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-05 DOI: 10.1016/j.bmcl.2025.130263

Xuqing Zhang, Qiaolin Deng, Harshil Dhruv, Matthew Tudor, Rakesh Nagilla, Larry J. Jolivette, Cory T. Rice, Peter Orth, Elham Behshad, Corey O. Strickland, Helai P. Mohammad, Zhihua Sui, E. Scott Priestley

{"title":"Overcoming CK1α liability in the discovery of a series of isoIndolinone Glutarimides as selective IKZF2 molecular glue degraders","authors":"Xuqing Zhang, Qiaolin Deng, Harshil Dhruv, Matthew Tudor, Rakesh Nagilla, Larry J. Jolivette, Cory T. Rice, Peter Orth, Elham Behshad, Corey O. Strickland, Helai P. Mohammad, Zhihua Sui, E. Scott Priestley","doi":"10.1016/j.bmcl.2025.130263","DOIUrl":"10.1016/j.bmcl.2025.130263","url":null,"abstract":"<div><div>IKZF2 (Ikaros Family Zinc Finger 2) is a transcription factor implicated in immune regulation and hematologic malignancies, where its dysregulation drives oncogenic programs, immune evasion, and therapy resistance. While targeted protein degradation (TPD) has emerged as a promising strategy, achieving selective IKZF2 degradation remains challenging due to off-target effects on structurally related neosubstrates such as IKZF1/3, SALL4, CK1α, and GSPT1. Here, we report the discovery of a novel series of isoindolinone glutarimide-based molecular glue degraders that selectively degrade IKZF2 while sparing CK1α and other neosubstrates. Through a structure-guided medicinal chemistry campaign, we identified divergent structure-activity relationships (SARs) enabling potent IKZF2 degradation with minimal off-target activity. The lead degrader (<strong>31</strong>) demonstrated high selectivity between IKZF2 and CK1α with acceptable oral bioavailability in mice. Our findings highlight the feasibility of developing precise IKZF2 degraders and provide a framework for optimizing selectivity in molecular glue design, offering a potential therapeutic strategy for IKZF2-dependent cancers.</div><div>2025 Elsevier Ltd. All rights reserved.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130263"},"PeriodicalIF":2.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143923267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 N-methylguanidine derivatives as a new type of potent pyruvate kinase M2 inhibitor 新型丙酮酸激酶M2抑制剂n -甲基胍衍生物的发现

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-05 DOI: 10.1016/j.bmcl.2025.130264

Weiguo Zhang , Zhenjiao Yang , Xingxing Li , Danfang Li , Jingyan Liu , Wanyi Liu , Wei Xie , Jian Liu , Yunzhang Cheng , Hao Yang , Xiuhong Lu

{"title":"Discovery of N-methylguanidine derivatives as a new type of potent pyruvate kinase M2 inhibitor","authors":"Weiguo Zhang , Zhenjiao Yang , Xingxing Li , Danfang Li , Jingyan Liu , Wanyi Liu , Wei Xie , Jian Liu , Yunzhang Cheng , Hao Yang , Xiuhong Lu","doi":"10.1016/j.bmcl.2025.130264","DOIUrl":"10.1016/j.bmcl.2025.130264","url":null,"abstract":"<div><div>Lung cancer is the leading cause of cancer-related mortality, with non-small cell lung cancer (NSCLC) accounting for 80–85 % of all cases. Thus, while challenging, the exploration of novel therapeutic agents for NSCLC treatment is highly desirable. Pyruvate kinase M2 (PKM2) has been closely associated with disease progression and metastasis in NSCLC, making it a promising therapeutic target. Herein, we report the discovery of a series of <em>N</em>-methylguanidine derivatives that demonstrated potent PKM2 inhibitory activity. In particular, <em>N′</em>-phenanthroline-substituted <em>N</em>-methyl guanidine exhibited notable PKM2 inhibition. Further testing demonstrated that compound <strong>16</strong> exhibited excellent inhibitory effects on A549 and HCC1833 NSCLC cell lines, with IC<sub>50</sub> values of 3.36 μM and 9.20 μM, respectively. <em>In vivo</em> antitumor studies further showed that compound <strong>16</strong> significantly inhibited tumor growth in human-derived NSCLC models and mouse lung adenocarcinoma models. Based on these findings, we propose <em>N′</em>-phenanthroline-substituted <em>N</em>-methylguanidine <strong>16</strong> as a promising novel PKM2 inhibitor with potential therapeutic applications for NSCLC.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130264"},"PeriodicalIF":2.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143923266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 TNG-6132, a potent, selective, and orally bioavailable USP1 inhibitor 发现TNG-6132，一种有效的，选择性的，口服生物可利用的USP1抑制剂

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-04-30 DOI: 10.1016/j.bmcl.2025.130262

Scott Throner, Tianshu Feng, Jannik N. Andersen, Madhavi Bandi, Justin L. Engel, Shanzhong Gong, Deepali Gotur, Lina Gu, Alan Huang, Katherine Lazarides, John P. Maxwell, Patrick McCarren, Brian J. McMillan, Truc V. Pham, Antoine Simoneau, Alice Tsai, Douglas A. Whittington, Erik Wilker, Minjie Zhang, Wenhai Zhang

{"title":"Discovery of TNG-6132, a potent, selective, and orally bioavailable USP1 inhibitor","authors":"Scott Throner, Tianshu Feng, Jannik N. Andersen, Madhavi Bandi, Justin L. Engel, Shanzhong Gong, Deepali Gotur, Lina Gu, Alan Huang, Katherine Lazarides, John P. Maxwell, Patrick McCarren, Brian J. McMillan, Truc V. Pham, Antoine Simoneau, Alice Tsai, Douglas A. Whittington, Erik Wilker, Minjie Zhang, Wenhai Zhang","doi":"10.1016/j.bmcl.2025.130262","DOIUrl":"10.1016/j.bmcl.2025.130262","url":null,"abstract":"<div><div>USP1 (ubiquitin-specific peptidase 1) is a deubiquitinating enzyme that has been identified as essential in <em>BRCA1/2</em> mutant cells and implicated in the DNA damage response. Inhibition of USP1 by small molecule inhibitors disrupts DNA repair and replication and is being pursued as a potential anticancer therapeutic in <em>BRCA1/2</em> mutant cancers. We report the discovery of an <em>in vitro</em> and <em>in vivo</em> USP1 inhibitor tool compound TNG-6132 (<strong>18</strong>), a reversible, allosteric inhibitor of USP1, which strongly inhibits USP1 enzymatic activity. This inhibitory effect translates into <em>in vitro</em> cellular viability defects in a <em>BRCA1</em>-mutant breast cancer cell line, as well as an <em>in vivo</em> pharmacodynamic (PD) response and tumor growth suppression in a mouse xenograft efficacy model. Additionally, we report an X-ray co-crystal structure of TNG-6132 (<strong>18</strong>) bound in the USP1-UAF1 complex, a result that furthered our understanding of the role played by key elements of the pharmacophore of this chemotype as well as its mechanism of inhibition of USP1.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130262"},"PeriodicalIF":2.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143912686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 of Isosteviol derivatives as potential anticancer agents, especially for ovarian Cancer: In vitro cytotoxicity, cell cycle arrest, network pharmacology and molecular docking study 异甜菊醇衍生物作为潜在抗癌药物的合成，特别是卵巢癌：体外细胞毒性、细胞周期阻滞、网络药理学和分子对接研究

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-04-29 DOI: 10.1016/j.bmcl.2025.130261

Yuxin Ding , Enxiao Wang , Lin Xing , Chaoyan Zhang , Ruilong Sheng , Wenhui Wu , Ruihua Guo

{"title":"Synthesis of Isosteviol derivatives as potential anticancer agents, especially for ovarian Cancer: In vitro cytotoxicity, cell cycle arrest, network pharmacology and molecular docking study","authors":"Yuxin Ding , Enxiao Wang , Lin Xing , Chaoyan Zhang , Ruilong Sheng , Wenhui Wu , Ruihua Guo","doi":"10.1016/j.bmcl.2025.130261","DOIUrl":"10.1016/j.bmcl.2025.130261","url":null,"abstract":"<div><div>Isosteviol is a tetracyclic diterpenoid from the hydrolysis of steviosidic acid, it exhibits a moderate inhibitory impact on tumor proliferation across various cancer types. Herein, we improved antitumor efficacy of isosteviol by modifying its reactive groups at C-16 and C-19 positions. A series of isosteviol derivatives <strong>2</strong>–<strong>17</strong>, were synthesized and characterized. Their anti-proliferative activities were evaluated in three human cancer cell lines (HCT116, SKOV3 and HepG2) by CCK-8 assay. The results showed that derivative <strong>10</strong> has strong cancer cell inhibitory activities (with IC<sub>50</sub> = 24.98 ± 1.82 μM for HCT116, IC<sub>50</sub> = 26.15 ± 0.05 μM for SKOV3 and IC<sub>50</sub> = 23.09 ± 0.31 μM for HepG2 cells). Accordingly, structure-activity relationships (SARs) of these isosteviol derivatives in ovarian cancer SKOV3 cells were discussed in detail. Moreover, derivative <strong>10</strong> has concentration-dependent cell cycle arrest at S-G2/M phases in SKOV3 cells, and it could greatly induce apoptosis. In addition, the targets of isosteviol against ovarian cancer were predicted and analyzed <em>via</em> network pharmacology. Then, molecular docking analysis showed that derivative <strong>10</strong> could interact with HSP90AA1 through its LYS-58 residues (docking energy: −8.96 kal/mol). The results suggested that derivative <strong>10</strong> might be employed as a promising drug candidate for anticancer chemotherapy.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130261"},"PeriodicalIF":2.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143908269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Design, synthesis and evaluation of novel cycloalkylthiophene-based aminopyrimidine derivatives as potent PLK1 inhibitors 新型环烷基噻吩基氨基嘧啶衍生物作为PLK1抑制剂的设计、合成和评价

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-04-29 DOI: 10.1016/j.bmcl.2025.130260

Meixue Ai , Yukang Lin , Xiaoyu Zhong , Zhongkai Zou , Pengcheng Diao , Yanting Zhang , Jingkao Chen , Peiliang Zhao , Zhibo Zhu

{"title":"Design, synthesis and evaluation of novel cycloalkylthiophene-based aminopyrimidine derivatives as potent PLK1 inhibitors","authors":"Meixue Ai , Yukang Lin , Xiaoyu Zhong , Zhongkai Zou , Pengcheng Diao , Yanting Zhang , Jingkao Chen , Peiliang Zhao , Zhibo Zhu","doi":"10.1016/j.bmcl.2025.130260","DOIUrl":"10.1016/j.bmcl.2025.130260","url":null,"abstract":"<div><div>PLK1 plays a pivotal role in cell-cycle regulation and has been well-characterized as a promising target for cancer therapy. Here, we synthesized a series of fused-thiophene based aminopyrimidine derivatives, and discovered a novel and potent PLK1 inhibitor compound <strong>7n</strong> with an IC<sub>50</sub> value of 38.5 nM. Analogue <strong>7n</strong> exhibited remarkable antiproliferative efficacy toward HepG2, Huh7, H1299, and A549 cells, and hasn't any noticeable cytotoxic activity on the non-tumoural cell line HEK-293. Further mechanism studies indicated <strong>7n</strong> arrested the cell cycle at the G2/M phase and induced apoptosis in HepG2 cells with a concentration-dependent manner. Molecular docking presented that <strong>7n</strong> could occupy well the ATP-binding site of PLK1 with a U-shaped conformation. Collectively, these results provide new insights into the further development of fused-thiophene based aminopyrimidines as PLK1 inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130260"},"PeriodicalIF":2.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143908268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Structure based design, synthesis and identification of novel covalent reversible dual TLR2/TLR9 small molecule antagonists 基于结构的新型共价可逆双TLR2/TLR9小分子拮抗剂的设计、合成与鉴定

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-04-26 DOI: 10.1016/j.bmcl.2025.130259

Srinivasa Reddy Natala , Agata Habas , Emily M. Stocking , Andrew Orry , Ruben Abagyan , Milan T. Makale , Wolfgang Wrasidlo

{"title":"Structure based design, synthesis and identification of novel covalent reversible dual TLR2/TLR9 small molecule antagonists","authors":"Srinivasa Reddy Natala , Agata Habas , Emily M. Stocking , Andrew Orry , Ruben Abagyan , Milan T. Makale , Wolfgang Wrasidlo","doi":"10.1016/j.bmcl.2025.130259","DOIUrl":"10.1016/j.bmcl.2025.130259","url":null,"abstract":"<div><div>Inflammation is a key driver of the onset and progression of neurodegenerative diseases and cancer and can be caused by aggregated proteins, injured neurons or synapses, dysregulation of inflammatory control mechanisms, and other factors. Tolllike receptors (TLRs) are important mediators of inflammatory pathways, and their activation leads to pro-inflammatory cytokine release by immune cells in the periphery or in the central nervous system (CNS). TLR2 and TLR9 are implicated in the inflammatory pathogenesis of CNS degenerative diseases such as Parkinson's Disease (PD) and amyotrophic lateral sclerosis (ALS). They are also held to be important in the etiology of certain malignancies like inflammatory pancreatic ductal adenocarcinoma and glioblastoma. Inactivation of TLR2/9 in animal models of neurodegeneration has reduced pathological markers and diminished neuronal loss, while in animal models of cancer it has suppressed tumors. Therefore, TLR2 and TLR9 may be potential targets for the treatment of neurodegenerative disorders and cancers. We identified for the first time a key binding locus in TLR2/9 TIR domain which guided reversible covalent drug (RCD) design of a novel, first-in class series of dual TLR2/9 antagonists. Sub-micromolar antagonist concentrations potently inhibited TLR2 and TLR9 signaling induced by TLR2/9 specific agonists. Importantly, this series of antagonists did not discernably activate other TLRs and exhibited favorable in-vitro ADME and safety. The analogs described here may help realize effective TLR2/9 antagonism as a viable therapeutic strategy for inflammation driven CNS diseases and various malignancies with an inflammatory etiology.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"124 ","pages":"Article 130259"},"PeriodicalIF":2.5,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143898811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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