A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs
A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs
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DOI：
10.1073/pnas.1408124111
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发表时间：
2014-09-23
影响因子：
11.1
通讯作者：
Steinmetz, Michel O.
中科院分区：
文献类型：
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作者：
Prota, Andrea E.;Bargsten, Katja;Steinmetz, Michel O.
最近抗体-药物偶联物（adc）在治疗癌症方面的成功，重新引起了人们对微管不稳定剂的兴趣。在这里，我们确定了微管蛋白和美丹辛之间复合物的高分辨率晶体结构，美丹辛是美国食品和药物管理局（FDA）批准用于治疗晚期乳腺癌的ADC的一部分。我们发现该药物与β -微管蛋白上的一个位点结合，该位点与长春花结构域不同，并阻断微管中纵向微管蛋白相互作用的形成。我们还解决了微管蛋白与根毒素变体和一期药物PM060184复合物的晶体结构。与生化和诱变数据一致，我们发现这两种化合物与美坦辛结合在同一位点，并且结构显示了这三种配体的共同药效团。我们的研究结果描述了临床相关药物抑制微管组装的独特分子机制。它们进一步为合理设计有效的微管不稳定剂提供了结构基础，从而为开发用于治疗癌症的下一代adc提供了机会。
The recent success of antibody-drug conjugates (ADCs) in the treatment of cancer has led to a revived interest in microtubule-destabilizing agents. Here, we determined the high-resolution crystal structure of the complex between tubulin and maytansine, which is part of an ADC that is approved by the US Food and Drug Administration (FDA) for the treatment of advanced breast cancer. We found that the drug binds to a site on beta-tubulin that is distinct from the vinca domain and that blocks the formation of longitudinal tubulin interactions in microtubules. We also solved crystal structures of tubulin in complex with both a variant of rhizoxin and the phase 1 drug PM060184. Consistent with biochemical and mutagenesis data, we found that the two compounds bound to the same site as maytansine and that the structures revealed a common pharmacophore for the three ligands. Our results delineate a distinct molecular mechanism of action for the inhibition of microtubule assembly by clinically relevant agents. They further provide a structural basis for the rational design of potent microtubule-destabilizing agents, thus opening opportunities for the development of next-generation ADCs for the treatment of cancer.