Selective Aurora A-TPX2 Interaction Inhibitors Have In Vivo Efficacy as Targeted Antimitotic Agents.

IF 5.3 2区材料科学 Q2 MATERIALS SCIENCE, MULTIDISCIPLINARY

ACS Applied Nano Materials Pub Date : 2024-09-12 Epub Date: 2024-08-27 DOI:10.1021/acs.jmedchem.4c01165

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

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.

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选择性极光 A-TPX2 相互作用抑制剂作为靶向抗锑药物在体内具有疗效

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。

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来源期刊

ACS Applied Nano Materials Multiple-

CiteScore

8.30

自引率

3.40%

发文量

1601

期刊介绍： ACS Applied Nano Materials is an interdisciplinary journal publishing original research covering all aspects of engineering, chemistry, physics and biology relevant to applications of nanomaterials. The journal is devoted to reports of new and original experimental and theoretical research of an applied nature that integrate knowledge in the areas of materials, engineering, physics, bioscience, and chemistry into important applications of nanomaterials.