Selective Aurora A-TPX2 Interaction Inhibitors Have In Vivo Efficacy as Targeted Antimitotic Agents,Journal of Medicinal Chemistry

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Selective Aurora A-TPX2 Interaction Inhibitors Have In Vivo Efficacy as Targeted Antimitotic Agents
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-27 , DOI: 10.1021/acs.jmedchem.4c01165
Simon R Stockwell ₁ , Duncan E Scott ₂ , Gerhard Fischer ₃ , Estrella Guarino ₁ , Timothy P C Rooney ₂ , Tzu-Shean Feng ₂ , Tommaso Moschetti ₃ , Rajavel Srinivasan ₂ , Esther Alza ₂ , Alice Asteian ₂ , Claudio Dagostin ₂ , Anna Alcaide ₂ , Mathieu Rocaboy ₃ , Beata Blaszczyk ₃ , Alicia Higueruelo ₃ , Xuelu Wang ₃ , Maxim Rossmann ₃ , Trevor R Perrior , Tom L Blundell ₃ , David R Spring ₂ , Grahame McKenzie ₁ , Chris Abell ₂ , John Skidmore ₂ , Ashok R Venkitaraman ₁ , Marko Hyvönen ₃

Affiliation

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.

中文翻译：

选择性 Aurora A-TPX2 相互作用抑制剂作为靶向抗有丝分裂剂具有体内功效

Aurora A 激酶是一种细胞分裂调节因子，经常在各种癌症中过度表达，引发基因组不稳定和抗有丝分裂化疗耐药。 Aurora A 的定位和酶活性通过其与纺锤体组装因子 TPX2 的相互作用进行调节。我们使用基于片段、结构引导的先导物发现来开发 Aurora A-TPX2 蛋白-蛋白相互作用 (PPI) 的小分子抑制剂。我们的先导化合物CAM2602抑制 Aurora A:TPX2 相互作用，以 19 nM 亲和力结合 Aurora A。 CAM2602具有口服生物利用度，引起药效生物标志物调节，并阻止肿瘤异种移植物的生长。与 ATP 竞争性抑制剂相比， CAM2602的作用机制新颖，并且对 Aurora A 的特异性高于 Aurora B。与我们发现 Aurora A 过度表达会导致紫杉烷耐药性的发现一致，这些抑制剂与紫杉醇协同抑制胰腺癌细胞的生长。我们的结果为靶向 Aurora A-TPX2 PPI 进行癌症治疗提供了蓝图，并表明这种作用模式具有广阔的临床应用前景。

更新日期：2024-08-27

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