ACS Medicinal Chemistry Letters最新文献_第4页

Discovery of Pyrazole-Containing 4-Arylindolines as Potent Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction 含吡唑的4-芳基喹啉作为程序性细胞死亡-1/程序性细胞死亡-配体-1相互作用的有效小分子抑制剂的发现

IF 4 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-08-08 DOI: 10.1021/acsmedchemlett.5c00423

Wensong Deng, Yuan Yang, Tairen Zhou, Xuanchi Zhu, Bing Xu, Xiaoyao Zhao, Kun Huang, Yanqi Jin, Lihui Wang* and Mingze Qin*,

{"title":"Discovery of Pyrazole-Containing 4-Arylindolines as Potent Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction","authors":"Wensong Deng, Yuan Yang, Tairen Zhou, Xuanchi Zhu, Bing Xu, Xiaoyao Zhao, Kun Huang, Yanqi Jin, Lihui Wang* and Mingze Qin*, ","doi":"10.1021/acsmedchemlett.5c00423","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00423","url":null,"abstract":"The development of small-molecule inhibitors targeting the programmed cell death-1(PD-1)/programmed cell death-ligand 1 (PD-L1) interaction has emerged as a promising strategy in tumor immunotherapy. In this study, a series of 4-arylindoline derivatives containing a pyrazole moiety were designed and synthesized through a medicinal chemistry campaign based on compound 1, a potent immunomodulator previously reported by our group. Among these, compound J29 was identified as the most promising inhibitor, exhibiting an IC50 value of 5.5 nM against the PD-1/PD-L1 interaction in a biochemical assay. In coculture models of tumor cells and T cells, J29 effectively promoted T-cell proliferation and restored their ability to kill tumor cells. Moreover, J29 showed significantly improved metabolic stability in human liver microsomes (HLMs) compared with compound 1. These findings indicate that J29 represents a promising lead compound for the further development of small-molecule PD-1/PD-L1 interaction inhibitors.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 9","pages":"1852–1859"},"PeriodicalIF":4.0,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036470","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 Piperidine Derivatives as NNMT Inhibitors for Treating Chronic Kidney Disease or Acute Kidney Injury 新型哌啶衍生物作为NNMT抑制剂治疗慢性肾脏疾病或急性肾损伤

IF 4 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-08-08 DOI: 10.1021/acsmedchemlett.5c00464

Ram W. Sabnis*,

引用次数: 0

Radiosynthesis and Biological Evaluation of a Small-Molecule Probe for Thyroid-Stimulating Hormone Receptor 促甲状腺激素受体小分子探针的放射合成及生物学评价

IF 4 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-08-07 DOI: 10.1021/acsmedchemlett.5c00210

Yuanyuan Zhou, Ji Tao, Yuanpeng Jiang, Aiyan Ji, Xiangning Luo, Jin Tian, Xuanyan Zhao, Kun Qian, Chunrong Qu, Renfei Wang*, Wen-Hua Chen* and Zhen Cheng*,

{"title":"Radiosynthesis and Biological Evaluation of a Small-Molecule Probe for Thyroid-Stimulating Hormone Receptor","authors":"Yuanyuan Zhou, Ji Tao, Yuanpeng Jiang, Aiyan Ji, Xiangning Luo, Jin Tian, Xuanyan Zhao, Kun Qian, Chunrong Qu, Renfei Wang*, Wen-Hua Chen* and Zhen Cheng*, ","doi":"10.1021/acsmedchemlett.5c00210","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00210","url":null,"abstract":"The thyroid-stimulating hormone receptor (TSHR) plays a pivotal role in regulating thyroid growth, function, synthesis, and secretion of thyroid hormones, with its overexpression linked to various diseases, especially in tumors. A novel TSHR-targeting small molecule agonist ML-109 with a nM potency has been developed. In this study, we radiolabeled ML-109 with radionuclide iodine-131 on the quinazolin-4-one ring to prepare 131I-ML-109, and its biological performance was further evaluated as a single-photon emission computed tomography radiotracer. The results displayed that 131I-ML-109 was prepared in high radiochemical purity >95% and moderate radiolabeling yield (∼40%). Further, 131I-ML-109 demonstrated a good tumor uptake capability in both K1 and 8305C xenograft models. Overall, this study has established the synthetic strategy for preparation of 131I-ML-109, highlighting that ML-109 is a promising molecular scaffold for developing TSHR targeted imaging probe. Further structural optimization is desired to improve the diagnostic performance of the next-generation probe.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 9","pages":"1740–1746"},"PeriodicalIF":4.0,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036468","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 Depression 新化合物作为5-HT2A激动剂治疗抑郁症

IF 4 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-08-07 DOI: 10.1021/acsmedchemlett.5c00461

Ram W. Sabnis*,

引用次数: 0

Transfer Hydrodehalogenation of Aryl Halides Mediated by [Pd(IPr*)(cinnamyl)Cl] [Pd(IPr*)（肉桂基）Cl]介导芳基卤化物的转移加氢脱卤

IF 4 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-08-06 DOI: 10.1021/acsmedchemlett.5c00377

Aleksei A. Logvinov, Eleonora Casillo, Matthieu Jouffroy* and Steven P. Nolan*,

引用次数: 0

Discovery of Small-Molecule Ligands for the E3 Ligase STUB1/CHIP from a DNA-Encoded Library Screen 从dna编码文库中发现E3连接酶STUB1/CHIP的小分子配体

IF 4 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-08-05 DOI: 10.1021/acsmedchemlett.5c00361

Simon C. C. Lucas*, Alexander G. Milbradt, Jason Breed, Erwin De Genst, Anne Jackson, Alisa Solovyeva, Bryony Ackroyd, Matthias R. Bauer, Juntai Liu, David Longmire, Dušan Petrović, Emma L. Rivers, Christopher Stubbs, Poppy Winlow, Sana Bazzaz, Paige Dickson, Diana Gikunju, Marie-Aude Guié, John P. Guilinger, Christopher D. Hupp, Rachael Jetson, Anthony D. Keefe, Katherine Nugai, John T. S. Yeoman, Ying Zhang, Xian Feng, Dequan Yu and Christopher Phillips,

{"title":"Discovery of Small-Molecule Ligands for the E3 Ligase STUB1/CHIP from a DNA-Encoded Library Screen","authors":"Simon C. C. Lucas*, Alexander G. Milbradt, Jason Breed, Erwin De Genst, Anne Jackson, Alisa Solovyeva, Bryony Ackroyd, Matthias R. Bauer, Juntai Liu, David Longmire, Dušan Petrović, Emma L. Rivers, Christopher Stubbs, Poppy Winlow, Sana Bazzaz, Paige Dickson, Diana Gikunju, Marie-Aude Guié, John P. Guilinger, Christopher D. Hupp, Rachael Jetson, Anthony D. Keefe, Katherine Nugai, John T. S. Yeoman, Ying Zhang, Xian Feng, Dequan Yu and Christopher Phillips, ","doi":"10.1021/acsmedchemlett.5c00361","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00361","url":null,"abstract":"STIP1 homology and U-box containing protein 1 (STUB1), also known as the C-terminus of Hsc70-interacting protein (CHIP), is an E3 ligase that plays a crucial role in removal of misfolded proteins via Hsc70. A DEL screen was run against CHIP to identify small-molecule binders. Two hits were identified that were confirmed by biochemical and biophysical techniques, including 2D NMR. X-ray crystal structures were obtained, which revealed binding to the peptide binding site. Fragment-based deconstruction indicated that hit 2 was a suitable starting point for optimization. During the optimization, an unexpected rearrangement of an oxadiazole from an array hit led to the exploration of an amide vector. This resulted in the discovery of compound 5, which is the most potent small-molecule ligand for CHIP identified to date and a suitable starting point for further optimization into a tool molecule or PROTAC warhead.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 8","pages":"1445–1451"},"PeriodicalIF":4.0,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144826114","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

Unveiling the Carbonic Anhydrase Inhibitory Profile of Aprocitentan: Kinetic and Structural Characterization 揭示碳酸酐酶抑制谱：动力学和结构表征

IF 4 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-08-01 DOI: 10.1021/acsmedchemlett.5c00421

Andrea Angeli*, Marta Ferraroni and Claudiu T. Supuran,

引用次数: 0

Novel Compounds for Treating Huntington’s Disease 治疗亨廷顿舞蹈病的新化合物

IF 4 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-07-31 DOI: 10.1021/acsmedchemlett.5c00442

Ram W. Sabnis*,

引用次数: 0

Synthesis and In Vitro/In Silico α-Glucosidase Inhibitory Study of Novel Ethanones Containing Naphthalene-Linked 1,2,4-Triazole 新型萘链1,2,4-三唑类乙酮的合成及体外/硅内α-葡萄糖苷酶抑制研究

IF 4 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-07-31 DOI: 10.1021/acsmedchemlett.5c00387

Cong T. Nguyen, Dung T.K. Hoang, Vu A. Truong, Loan T.K. Nguyen, Phi C. Dinh, Dung H.A. Mai*, Duc T. Le* and Nam N. Pham*,

{"title":"Synthesis and In Vitro/In Silico α-Glucosidase Inhibitory Study of Novel Ethanones Containing Naphthalene-Linked 1,2,4-Triazole","authors":"Cong T. Nguyen, Dung T.K. Hoang, Vu A. Truong, Loan T.K. Nguyen, Phi C. Dinh, Dung H.A. Mai*, Duc T. Le* and Nam N. Pham*, ","doi":"10.1021/acsmedchemlett.5c00387","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00387","url":null,"abstract":"Type 2 diabetes mellitus is a chronic-metabolic disorder characterized by insulin resistance, resulting in persistent hyperglycemia and severe complications. α-Glucosidase inhibitors (AGIs) effectively control postprandial blood glucose level by delaying carbohydrate digestion. This study reports the synthesis of novel naphthalene-linked 1,2,4-triazole-bearing ethanones (5a–e and 7a–f) as potential AGIs. Enzymatic assay demonstrated significantly superior α-glucosidase inhibitory potency of aryl-substituted derivatives (7a−f) compared to ethyl-substituted analogs (5a−e), highlighting the advance of aromatic substituents. Compounds 7b and 7c exhibited exceptional inhibitory activity (IC50 = 9.23–9.61 μM), conferring 37-fold more potency than voglibose. Molecular docking and dynamics simulations indicated predominant π-π stacking and hydrophobic interactions contributing to their stable enzyme binding. MM/GBSA binding-affinity calculation further supported their enhanced binding affinity, providing mechanistic insights into their potent activity. Collectively, these findings highlight the promise of naphthalene- and 1,2,4-triazole-bearing ethanones for the development of effective antidiabetic therapies.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 8","pages":"1676–1681"},"PeriodicalIF":4.0,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144826231","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 Peptides as GIPR/GLP-1R/GCGR Triagonists for Treating Type 2 Diabetes Mellitus 新型多肽作为GIPR/GLP-1R/GCGR三角激动剂治疗2型糖尿病

IF 4 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-07-31 DOI: 10.1021/acsmedchemlett.5c00435

Qilong Hu, and , Steven H. Liang*,

引用次数: 0