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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疗效。

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

机构信息

Medical Research Council Cancer Unit, University of Cambridge, Cambridge CB2 0XZ, U.K.

Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.

出版信息

J Med Chem. 2024 Sep 12;67(17):15521-15536. doi: 10.1021/acs.jmedchem.4c01165. Epub 2024 Aug 27.

DOI:10.1021/acs.jmedchem.4c01165
PMID:39190548
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11403621/
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, , inhibits Aurora A:TPX2 interaction, binding Aurora A with 19 nM affinity. exhibits oral bioavailability, causes pharmacodynamic biomarker modulation, and arrests the growth of tumor xenografts. 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.

摘要

极光激酶 A 是一种细胞分裂调节因子，在各种癌症中经常过表达，引发基因组不稳定和对抗有丝分裂化疗的耐药性。极光激酶 A 的定位和酶活性受其与纺锤体组装因子 TPX2 的相互作用调节。我们使用基于片段的、结构指导的先导发现方法来开发极光激酶 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 ，抑制极光激酶 A:TPX2 相互作用，以 19 nM 的亲和力与极光激酶 A 结合。 具有口服生物利用度，引起药效生物标志物的调节，并阻止肿瘤异种移植物的生长。 与 ATP 竞争性抑制剂相比， 作用机制新颖，对极光激酶 A 比对极光激酶 B 具有高度特异性。与我们发现的极光激酶 A 过表达导致紫杉醇耐药的结果一致，这些抑制剂与紫杉醇协同作用，抑制胰腺癌细胞的生长。我们的研究结果为针对 Aurora A-TPX2 PPI 进行癌症治疗提供了蓝图，并为这种作用模式的临床应用提供了有希望的依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/941b/11403621/6027c587d605/jm4c01165_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/941b/11403621/f8797bb11656/jm4c01165_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/941b/11403621/a2583f29534a/jm4c01165_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/941b/11403621/2fe3edf790b9/jm4c01165_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/941b/11403621/e0adf6c9a317/jm4c01165_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/941b/11403621/6027c587d605/jm4c01165_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/941b/11403621/f8797bb11656/jm4c01165_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/941b/11403621/a2583f29534a/jm4c01165_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/941b/11403621/2fe3edf790b9/jm4c01165_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/941b/11403621/e0adf6c9a317/jm4c01165_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/941b/11403621/6027c587d605/jm4c01165_0005.jpg

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