Simon R Stockwell, Duncan E Scott, Gerhard Fischer, Estrella Guarino, Timothy P C Rooney, Tzu-Shean Feng, Tommaso Moschetti, Rajavel Srinivasan, Esther Alza, Alice Asteian, Claudio Dagostin, Anna Alcaide, Mathieu Rocaboy, Beata Blaszczyk, Alicia Higueruelo, Xuelu Wang, Maxim Rossmann, Trevor R Perrior, Tom L Blundell, David R Spring, Grahame McKenzie, Chris Abell, John Skidmore, Ashok R Venkitaraman, Marko Hyvönen
{"title":"Selective Aurora A-TPX2 Interaction Inhibitors Have <i>In Vivo</i> Efficacy as Targeted Antimitotic Agents.","authors":"Simon R Stockwell, Duncan E Scott, Gerhard Fischer, Estrella Guarino, Timothy P C Rooney, Tzu-Shean Feng, Tommaso Moschetti, Rajavel Srinivasan, Esther Alza, Alice Asteian, Claudio Dagostin, Anna Alcaide, Mathieu Rocaboy, Beata Blaszczyk, Alicia Higueruelo, Xuelu Wang, Maxim Rossmann, Trevor R Perrior, Tom L Blundell, David R Spring, Grahame McKenzie, Chris Abell, John Skidmore, Ashok R Venkitaraman, Marko Hyvönen","doi":"10.1021/acs.jmedchem.4c01165","DOIUrl":null,"url":null,"abstract":"<p><p>Aurora A kinase, a cell division regulator, is frequently overexpressed in various cancers, provoking genome instability and resistance to antimitotic chemotherapy. Localization and enzymatic activity of Aurora A are regulated by its interaction with the spindle assembly factor TPX2. We have used fragment-based, structure-guided lead discovery to develop small molecule inhibitors of the Aurora A-TPX2 protein-protein interaction (PPI). Our lead compound, <b>CAM2602</b>, inhibits Aurora A:TPX2 interaction, binding Aurora A with 19 nM affinity. <b>CAM2602</b> exhibits oral bioavailability, causes pharmacodynamic biomarker modulation, and arrests the growth of tumor xenografts. <b>CAM2602</b> acts by a novel mechanism compared to ATP-competitive inhibitors and is highly specific to Aurora A over Aurora B. Consistent with our finding that Aurora A overexpression drives taxane resistance, these inhibitors synergize with paclitaxel to suppress the outgrowth of pancreatic cancer cells. Our results provide a blueprint for targeting the Aurora A-TPX2 PPI for cancer therapy and suggest a promising clinical utility for this mode of action.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11403621/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.4c01165","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/27 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
Aurora A kinase, a cell division regulator, is frequently overexpressed in various cancers, provoking genome instability and resistance to antimitotic chemotherapy. Localization and enzymatic activity of Aurora A are regulated by its interaction with the spindle assembly factor TPX2. We have used fragment-based, structure-guided lead discovery to develop small molecule inhibitors of the Aurora A-TPX2 protein-protein interaction (PPI). Our lead compound, CAM2602, inhibits Aurora A:TPX2 interaction, binding Aurora A with 19 nM affinity. CAM2602 exhibits oral bioavailability, causes pharmacodynamic biomarker modulation, and arrests the growth of tumor xenografts. CAM2602 acts by a novel mechanism compared to ATP-competitive inhibitors and is highly specific to Aurora A over Aurora B. Consistent with our finding that Aurora A overexpression drives taxane resistance, these inhibitors synergize with paclitaxel to suppress the outgrowth of pancreatic cancer cells. Our results provide a blueprint for targeting the Aurora A-TPX2 PPI for cancer therapy and suggest a promising clinical utility for this mode of action.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.