The prolyl isomerase PIN1, a critical modifier of multiple signalling pathways, is overexpressed in the majority of cancers and its activity strongly contributes to tumour initiation and progression. Inactivation of PIN1 function conversely curbs tumour growth and cancer stem cell expansion, restores chemosensitivity and blocks metastatic spread, thus providing the rationale for a therapeutic strategy based on PIN1 inhibition. Notwithstanding, potent PIN1 inhibitors are still missing from the arsenal of anti-cancer drugs. By a mechanism-based screening, we have identified a novel covalent PIN1 inhibitor, KPT-6566, able to selectively inhibit PIN1 and target it for degradation. We demonstrate that KPT-6566 covalently binds to the catalytic site of PIN1. This interaction results in the release of a quinone-mimicking drug that generates reactive oxygen species and DNA damage, inducing cell death specifically in cancer cells. Accordingly, KPT-6566 treatment impairs PIN1-dependent cancer phenotypes in vitro and growth of lung metastasis in vivo.

译文

脯氨酰异构酶PIN1是多种信号通路的关键修饰因子,在大多数癌症中过表达,其活性强烈有助于肿瘤的发生和发展。PIN1功能的失活反过来抑制肿瘤生长和癌症干细胞的扩增,恢复化学敏感性并阻止转移扩散,从而为基于PIN1抑制的治疗策略提供了依据。尽管如此,抗癌药物库中仍然缺少有效的PIN1抑制剂。通过基于机制的筛选,我们已经确定了一种新型的共价PIN1抑制剂,KPT-6566,能够选择性地抑制PIN1并靶向其降解。我们证明了KPT-6566与pin1的催化位点共价结合。这种相互作用导致释放出模拟醌的药物,该药物会产生活性氧和DNA损伤,从而在癌细胞中特定诱导细胞死亡。因此,KPT-6566治疗损害体外PIN1-dependent癌症表型和体内肺转移的生长。

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