Target identification of bioactive compounds is critical for understanding their mechanism of action. We previously discovered a novel pyrroloquinazoline compound LBL1 with significant anticancer activity. However, its molecular targets remain to be established. Herein, we developed a clickable photoaffinity probe based on LBL1. Using extensive chemical, biochemical, and cellular studies with this probe and LBL1, we found that LBL1 targets nuclear lamins, which are type V intermediate filament (IF) proteins. Further studies showed that LBL1 binds to the coiled-coil domain of lamin A. These results revealed that IF proteins can also be targeted with appropriate small molecules besides two other cytoskeletal proteins actin filaments and microtubules, providing a novel avenue to investigate lamin biology and a novel strategy to develop distinct anticancer therapies.

中文翻译：

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抗癌吡咯并喹唑啉LBL1靶向核纤层蛋白

生物活性化合物的目标识别对于理解其作用机理至关重要。我们以前发现了一种新型的具有显着抗癌活性的吡咯并喹唑啉化合物LBL1。但是，其分子靶标仍有待确定。本文中，我们开发了基于LBL1的可点击光亲和探针。通过对该探针和LBL1进行广泛的化学，生物化学和细胞研究，我们发现LBL1靶向核纤层蛋白，它们是V型中间丝（IF）蛋白。进一步的研究表明，LBL1 这些结果表明，除了两个其他细胞骨架蛋白肌动蛋白丝和微管外，IF蛋白还可以用适当的小分子靶向IF蛋白，从而为研究lamin生物学提供了新途径，并为开发独特的策略提供了新的策略。抗癌疗法。