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
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引用次数: 0
摘要
极光 A 激酶是一种细胞分裂调节因子,在各种癌症中经常过度表达,导致基因组不稳定,并对抗抑郁化疗产生抗药性。Aurora A 的定位和酶活性受其与纺锤体组装因子 TPX2 的相互作用调控。我们利用基于片段、结构引导的先导化合物发现技术,开发了 Aurora A-TPX2 蛋白相互作用(PPI)的小分子抑制剂。我们的先导化合物 CAM2602 可抑制 Aurora A:TPX2 相互作用,与 Aurora A 的结合亲和力为 19 nM。CAM2602 具有口服生物利用度,可引起药效学生物标志物调节,并能抑制肿瘤异种移植的生长。与 ATP 竞争性抑制剂相比,CAM2602 的作用机制新颖,对 Aurora A 的特异性高于 Aurora B。与我们发现的 Aurora A 过表达会导致紫杉类药物耐药性一致,这些抑制剂与紫杉醇协同抑制胰腺癌细胞的生长。我们的研究结果为靶向 Aurora A-TPX2 PPI 治疗癌症提供了一个蓝图,并表明这种作用模式具有广阔的临床应用前景。
Selective Aurora A-TPX2 Interaction Inhibitors Have In Vivo Efficacy as Targeted Antimitotic Agents.
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.