ACS Medicinal Chemistry Letters最新文献_第2页

Development of Novel Gastrin-Releasing Peptide Receptor-Targeted Radioligand with Albumin Binder to Improve Accumulation in Tumor 新型胃泌素释放肽受体靶向白蛋白结合物的研究进展

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-25 DOI: 10.1021/acsmedchemlett.5c0003210.1021/acsmedchemlett.5c00032

Shohei Tsuchihashi, Kazuma Nakashima, Hiroyuki Watanabe and Masahiro Ono*,

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引用次数: 0

Novel Spirocyclic WRN Helicase Inhibitors for Treating Cancer 新型螺旋环WRN解旋酶抑制剂治疗癌症

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-25 DOI: 10.1021/acsmedchemlett.5c0021610.1021/acsmedchemlett.5c00216

Ram W. Sabnis*,

引用次数: 0

Introducing the Potential Binding Interface between the TRAIL-Mimicking Peptide and DR5 via Alanine Scan. 通过丙氨酸扫描介绍trail模拟肽与DR5之间的潜在结合界面。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-25 eCollection Date: 2025-05-08 DOI: 10.1021/acsmedchemlett.5c00071

Nitesh Mani Tripathi, Arnab Chowdhury, Neelam Verma, Anupam Bandyopadhyay

{"title":"Introducing the Potential Binding Interface between the TRAIL-Mimicking Peptide and DR5 via Alanine Scan.","authors":"Nitesh Mani Tripathi, Arnab Chowdhury, Neelam Verma, Anupam Bandyopadhyay","doi":"10.1021/acsmedchemlett.5c00071","DOIUrl":"10.1021/acsmedchemlett.5c00071","url":null,"abstract":"Here we harnessed the unexplored binding interface between the 16-residue peptide (P) agonist and death receptor 5 (DR5). P is a solitary peptide ligand that mimics TRAIL (the natural ligand to death receptor) and is reported to control cancer growth in vivo selectively. We delved into the strategic merging of experimental and in silico structure-activity studies via the alanine scanning mutagenesis of P, wherein the disulfide bond was kept intact for structural integrity. Antiproliferative activity studies with these synthetic mutants on HCT116 cells enabled the mapping of the interaction engagement of each residue. Further, in silico docking and MD simulations led us to interpret and model the 3D interface of the binding site. Notably, Trp1, Leu4, Arg7, Ile8, Gln12, and Arg15 were projected experimentally as \"hot-spot\" residues crucial for primary interactions with DR5, which is predominantly supported via in silico investigations. This study is pivotal for developing new-generation peptide agonists that induce death receptor-mediated apoptosis.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 5","pages":"829-836"},"PeriodicalIF":3.5,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950968","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

Development of Novel Gastrin-Releasing Peptide Receptor-Targeted Radioligand with Albumin Binder to Improve Accumulation in Tumor. 新型胃泌素释放肽受体靶向白蛋白结合物的研究进展。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-25 eCollection Date: 2025-05-08 DOI: 10.1021/acsmedchemlett.5c00032

Shohei Tsuchihashi, Kazuma Nakashima, Hiroyuki Watanabe, Masahiro Ono

{"title":"Development of Novel Gastrin-Releasing Peptide Receptor-Targeted Radioligand with Albumin Binder to Improve Accumulation in Tumor.","authors":"Shohei Tsuchihashi, Kazuma Nakashima, Hiroyuki Watanabe, Masahiro Ono","doi":"10.1021/acsmedchemlett.5c00032","DOIUrl":"10.1021/acsmedchemlett.5c00032","url":null,"abstract":"Gastrin-releasing peptide receptor (GRPR) is a promising target for cancer radiotheranostics combining nuclear imaging with targeted radionuclide therapy. Improving the accumulation of radioligands in tumors by introducing an albumin binder (ALB) is useful to promote the efficacy of radiotheranostics. In this study, we designed and synthesized a novel GRPR-targeted radioligand [111In]In-AMTG-DA1 containing an ALB moiety to improve tumor accumulation. [111In]In-AMTG-DA1 showed marked binding ability to albumin, high affinity for GRPR, and high-level stability in vitro. In biodistribution studies, the tumor accumulation of [111In]In-AMTG-DA1 was much higher than that of the control ligand without an ALB moiety. The introduction of ALB increased the tumor area under the curve (AUC) value of [111In]In-AMTG-DA1 by 3.5 times. In a single-photon emission computed tomography (SPECT) study, [111In]In-AMTG-DA1 visualized a GRPR-expressing tumor clearly at 24 h postinjection. Our findings suggest the favorable pharmacokinetics of [111In]In-AMTG-DA1 as a GRPR-targeted radioligand exhibiting a high-level accumulation in tumors.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 5","pages":"797-803"},"PeriodicalIF":3.5,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951217","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

Novel Spirocyclic WRN Helicase Inhibitors for Treating Cancer. 新型螺旋环WRN解旋酶抑制剂治疗癌症。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-25 eCollection Date: 2025-05-08 DOI: 10.1021/acsmedchemlett.5c00216

Ram W Sabnis

引用次数: 0

Novel Piperidine Substituted Pyrazolopyrimidine Derivatives as SGK1 Inhibitors for Treating Cardiovascular Diseases. 新型哌啶取代吡唑嘧啶衍生物作为SGK1抑制剂治疗心血管疾病。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-25 eCollection Date: 2025-05-08 DOI: 10.1021/acsmedchemlett.5c00217

Ram W Sabnis

引用次数: 0

Virtual High-Throughput Screening of Ligands for Disrupting PRMT5/pICLn Interaction in Prostate Cancer Cells. 干扰前列腺癌细胞中PRMT5/pICLn相互作用的虚拟高通量配体筛选

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-25 eCollection Date: 2025-05-08 DOI: 10.1021/acsmedchemlett.5c00126

Zhihang Shen, Gustavo Seabra, Chenglong Li

{"title":"Virtual High-Throughput Screening of Ligands for Disrupting PRMT5/pICLn Interaction in Prostate Cancer Cells.","authors":"Zhihang Shen, Gustavo Seabra, Chenglong Li","doi":"10.1021/acsmedchemlett.5c00126","DOIUrl":"10.1021/acsmedchemlett.5c00126","url":null,"abstract":"Prostate cancer (PC) is the most commonly diagnosed cancer in men worldwide. While androgen deprivation therapy (ADT) is initially effective, many patients develop resistance, progressing to castration-resistant prostate cancer (CRPC). Recent studies have identified the interaction between PRMT5 (protein arginine methyltransferase 5) and pICLn as a promising therapeutic target, as it promotes the transcription of double-strand break (DSB) repair genes that contribute to therapy resistance. To target this pathway, a screening campaign identified J021-0199 as a potential hit compound that disrupts the PRMT5/pICLn interaction. Biochemical assays demonstrated that J021-0199 binds to the N-terminal TIM barrel domain of PRMT5. In CRPC cell lines (LNCaP and 22Rv1), J021-0199 selectively inhibited cancer cell growth. qPCR analysis further revealed downregulation of DNA damage response (DDR) genes involved in homologous recombination, nonhomologous end joining, and G2 arrest. These results support J021-0199 as a promising lead compound for overcoming resistance in CRPC.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 5","pages":"875-879"},"PeriodicalIF":3.5,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951888","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

Introducing the Potential Binding Interface between the TRAIL-Mimicking Peptide and DR5 via Alanine Scan 通过丙氨酸扫描介绍trail模拟肽与DR5之间的潜在结合界面

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-25 DOI: 10.1021/acsmedchemlett.5c0007110.1021/acsmedchemlett.5c00071

Nitesh Mani Tripathi, Arnab Chowdhury, Neelam Verma and Anupam Bandyopadhyay*,

{"title":"Introducing the Potential Binding Interface between the TRAIL-Mimicking Peptide and DR5 via Alanine Scan","authors":"Nitesh Mani Tripathi, Arnab Chowdhury, Neelam Verma and Anupam Bandyopadhyay*, ","doi":"10.1021/acsmedchemlett.5c0007110.1021/acsmedchemlett.5c00071","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00071https://doi.org/10.1021/acsmedchemlett.5c00071","url":null,"abstract":"Here we harnessed the unexplored binding interface between the 16-residue peptide (P) agonist and death receptor 5 (DR5). P is a solitary peptide ligand that mimics TRAIL (the natural ligand to death receptor) and is reported to control cancer growth in vivo selectively. We delved into the strategic merging of experimental and in silico structure–activity studies via the alanine scanning mutagenesis of P, wherein the disulfide bond was kept intact for structural integrity. Antiproliferative activity studies with these synthetic mutants on HCT116 cells enabled the mapping of the interaction engagement of each residue. Further, in silico docking and MD simulations led us to interpret and model the 3D interface of the binding site. Notably, Trp1, Leu4, Arg7, Ile8, Gln12, and Arg15 were projected experimentally as “hot-spot” residues crucial for primary interactions with DR5, which is predominantly supported via in silico investigations. This study is pivotal for developing new-generation peptide agonists that induce death receptor-mediated apoptosis.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 5","pages":"829–836 829–836"},"PeriodicalIF":3.5,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917122","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 Substituted Pyrazolopyrimidine Derivatives as SGK1 Inhibitors for Treating Cardiovascular Diseases 新型哌啶取代吡唑嘧啶衍生物作为SGK1抑制剂治疗心血管疾病

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-25 DOI: 10.1021/acsmedchemlett.5c0021710.1021/acsmedchemlett.5c00217

Ram W. Sabnis*,

引用次数: 0

Gold(I) N-Heterocyclic Carbene Complexes as Ferroptosis Inducing Anticancer Agents. 金(I) n -杂环卡宾配合物作为诱导铁下垂的抗癌剂。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-24 eCollection Date: 2025-05-08 DOI: 10.1021/acsmedchemlett.5c00096

Evelyn Schlegel, Zisis Papadopoulos, Nicolás Montesdeoca, Vladislav A Voloshkin, Steven P Nolan, Stephan A Hahn, Thomas Scattolin, Johannes Karges

引用次数: 0