ACS Medicinal Chemistry Letters最新文献_第5页

Design, Synthesis, and Biological Evaluation of Chiral-Proline Derivatives as Novel HSP90 Inhibitors

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-22 DOI: 10.1021/acsmedchemlett.4c0055010.1021/acsmedchemlett.4c00550

Chao Zhang, Shuang Cui, Jialin Mu, Kexin Liu, Yuanxun Wang, Hongyu Zhao, Yuguang Mu, Youming Zhang*, Xiaobo Wan* and Chun Song*,

{"title":"Design, Synthesis, and Biological Evaluation of Chiral-Proline Derivatives as Novel HSP90 Inhibitors","authors":"Chao Zhang, Shuang Cui, Jialin Mu, Kexin Liu, Yuanxun Wang, Hongyu Zhao, Yuguang Mu, Youming Zhang*, Xiaobo Wan* and Chun Song*, ","doi":"10.1021/acsmedchemlett.4c0055010.1021/acsmedchemlett.4c00550","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00550https://doi.org/10.1021/acsmedchemlett.4c00550","url":null,"abstract":"Heat shock protein 90 (HSP90) is a promising target for oncology therapeutics. Over the past decades, several small molecule inhibitors have demonstrated significant antitumor activity in clinical trials. However, nearly all HSP90 inhibitors in clinical trials have failed due to toxicity or insufficient efficacy. By leveraging crystal structures and current knowledge, we synthesized and evaluated a series of novel derivatives with potent HSP90 inhibitory activity, optimized from resorcinol-based (2R, 4R)-4-phenylproline. These derivatives underwent SAR analysis, leading to the discovery of compounds 16t and 20m, which exhibit strong HSP90 binding affinity and antiproliferative effects against MCF-7, HCT116, SKBr3, K562, and A549 cell lines. Nevertheless, further optimization of derivatives 16t and 20m was required to enhance their oral bioavailability and isoform selectivity. Our findings provide valuable insights for the ongoing research into selective HSP90α inhibitors and lay a foundation for developing next-generation HSP90α inhibitors and antitumor agents.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"301–310 301–310"},"PeriodicalIF":3.5,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394311","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

Eperisone Analogs, Rescuers of MiaB Defects As a Prokaryotic Homologue of CDKAL1, Suppress Blood Glucose Elevation in Rats

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-17 DOI: 10.1021/acsmedchemlett.4c0056010.1021/acsmedchemlett.4c00560

Manabu Tejima, Tomoko Hashimoto, Osamu Ohno, Tomoyuki Hoshina, Kotaro Takasaki, Shintaro Taniguchi, Kanako Nakamura, Fan-Yan Wei, Kazuhito Tomizawa and Kenji Matsuno*,

{"title":"Eperisone Analogs, Rescuers of MiaB Defects As a Prokaryotic Homologue of CDKAL1, Suppress Blood Glucose Elevation in Rats","authors":"Manabu Tejima, Tomoko Hashimoto, Osamu Ohno, Tomoyuki Hoshina, Kotaro Takasaki, Shintaro Taniguchi, Kanako Nakamura, Fan-Yan Wei, Kazuhito Tomizawa and Kenji Matsuno*, ","doi":"10.1021/acsmedchemlett.4c0056010.1021/acsmedchemlett.4c00560","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00560https://doi.org/10.1021/acsmedchemlett.4c00560","url":null,"abstract":"Cdk5 regulatory associated protein 1-like 1 (CDKAL1) is one of the most reliable risk genes for type 2 diabetes mellitus (T2DM). Because CDKAL1 controls glucose-induced insulin secretion by KATP channel responsiveness and faithful decoding of Lys codons to prevent mistranslation in pancreatic β-cells, a rescuer of CDKAL1 defects is expected as a new antidiabetes drug. We found that eperisone analogs effectively rescued mistranslation in a MiaB-deficient Escherichia coli dual-luciferase reporter gene system (MiaB is a prokaryotic homologue of eukaryotic CDKAL1). Among them, compounds 1f and 1t demonstrated significant antihyperglycemic efficacy in an oral glucose tolerance test by subcutaneous administration in Wister rats, along with a significant enhancement of insulin secretion in the MIN6 insulinoma cell line without cytotoxicity. These results indicate that CDKAL1 could be a viable molecular target for a new anti-T2DM medication.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"311–316 311–316"},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394209","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

Eperisone Analogs, Rescuers of MiaB Defects As a Prokaryotic Homologue of CDKAL1, Suppress Blood Glucose Elevation in Rats.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-17 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.4c00560

Manabu Tejima, Tomoko Hashimoto, Osamu Ohno, Tomoyuki Hoshina, Kotaro Takasaki, Shintaro Taniguchi, Kanako Nakamura, Fan-Yan Wei, Kazuhito Tomizawa, Kenji Matsuno

{"title":"Eperisone Analogs, Rescuers of MiaB Defects As a Prokaryotic Homologue of CDKAL1, Suppress Blood Glucose Elevation in Rats.","authors":"Manabu Tejima, Tomoko Hashimoto, Osamu Ohno, Tomoyuki Hoshina, Kotaro Takasaki, Shintaro Taniguchi, Kanako Nakamura, Fan-Yan Wei, Kazuhito Tomizawa, Kenji Matsuno","doi":"10.1021/acsmedchemlett.4c00560","DOIUrl":"10.1021/acsmedchemlett.4c00560","url":null,"abstract":"Cdk5 regulatory associated protein 1-like 1 (CDKAL1) is one of the most reliable risk genes for type 2 diabetes mellitus (T2DM). Because CDKAL1 controls glucose-induced insulin secretion by KATP channel responsiveness and faithful decoding of Lys codons to prevent mistranslation in pancreatic β-cells, a rescuer of CDKAL1 defects is expected as a new antidiabetes drug. We found that eperisone analogs effectively rescued mistranslation in a MiaB-deficient Escherichia coli dual-luciferase reporter gene system (MiaB is a prokaryotic homologue of eukaryotic CDKAL1). Among them, compounds 1f and 1t demonstrated significant antihyperglycemic efficacy in an oral glucose tolerance test by subcutaneous administration in Wister rats, along with a significant enhancement of insulin secretion in the MIN6 insulinoma cell line without cytotoxicity. These results indicate that CDKAL1 could be a viable molecular target for a new anti-T2DM medication.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"311-316"},"PeriodicalIF":3.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447381","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 Bicyclic Amines as CDK2 Inhibitors for Treating Metastatic Breast Cancer or Metastatic Lung Cancer.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-16 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.5c00005

Ram W Sabnis

引用次数: 0

Novel Bicyclic Amines as CDK2 Inhibitors for Treating Metastatic Breast Cancer or Metastatic Lung Cancer

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-16 DOI: 10.1021/acsmedchemlett.5c0000510.1021/acsmedchemlett.5c00005

Ram W. Sabnis*,

引用次数: 0

Novel Carbocyclic Phenylpyrrolidinone Urea Compounds as FPR2 Agonists for Treating Atherosclerosis and Heart Failure

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-10 DOI: 10.1021/acsmedchemlett.4c0061410.1021/acsmedchemlett.4c00614

Ram W. Sabnis*,

引用次数: 0

Novel Carbocyclic Phenylpyrrolidinone Urea Compounds as FPR2 Agonists for Treating Atherosclerosis and Heart Failure.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-10 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.4c00614

Ram W Sabnis

引用次数: 0

Novel 6-Substituted-3-Phenylisoindolin-1-ones as Cbl-B Inhibitors for Treating Cancer.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-09 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.4c00628

Ram W Sabnis

引用次数: 0

Clozapine as an E3 Ligand for PROTAC Technology

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-08 DOI: 10.1021/acsmedchemlett.4c0050010.1021/acsmedchemlett.4c00500

Reina Takano, Nobumichi Ohoka*, Takashi Kurohara, Noriaki Arakawa, Kenji Ohgane, Takao Inoue, Hidetomo Yokoo* and Yosuke Demizu*,

{"title":"Clozapine as an E3 Ligand for PROTAC Technology","authors":"Reina Takano, Nobumichi Ohoka*, Takashi Kurohara, Noriaki Arakawa, Kenji Ohgane, Takao Inoue, Hidetomo Yokoo* and Yosuke Demizu*, ","doi":"10.1021/acsmedchemlett.4c0050010.1021/acsmedchemlett.4c00500","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00500https://doi.org/10.1021/acsmedchemlett.4c00500","url":null,"abstract":"New ubiquitin ligase (E3) ligands are crucial for developing proteolysis-targeting chimeras (PROTACs) to induce the degradation of a target protein. In this study, we developed a PROTAC using the antipsychotic drug clozapine as a new E3 ligand. First, a clozapine PROTAC targeting a model target HaloTag protein (Halo-PEG-Clozapine) was synthesized, and the PROTAC induced degradation of the HaloTag-fused protein in a cell culture system. Another clozapine PROTAC targeting the cancer therapeutic target estrogen receptor α (ERα) (Tamoxifen-PEG-Clozapine) was synthesized and induced degradation of the ERα protein in MCF-7 breast cancer cells. Experiments with inhibitors and siRNAs showed that Tamoxifen-PEG-Clozapine degraded ERα via a ubiquitin-proteasome system that uses the ubiquitin protein ligase E3 component N-recognin 5. These results indicate that clozapine is a promising E3 ligand that may expand the molecular design of PROTACs, contributing to the advancement of drug discovery by facilitating the degradation of disease-related proteins.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 2","pages":"258–262 258–262"},"PeriodicalIF":3.5,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394283","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 Pyridine Derivatives as 5-HT2A Agonists for Treating Psychiatric Disorders.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-01-08 eCollection Date: 2025-02-13 DOI: 10.1021/acsmedchemlett.4c00629

Ram W Sabnis, Anika R Sabnis

引用次数: 0