由于它在癌症中的过度表达，重点关注非受体酪氨酸激酶和支架蛋白的细胞内信号调节蛋白——焦点粘附激酶（FAK）的药物发现已成为一种有吸引力的药物靶点。虽然药物发现的努力主要集中在以FAK激酶活性为靶点，但FAK抑制剂在临床试验中作为单一药物的疗效失败。在这里，利用结构指导的设计，我们报告了开发出一种选择性FAK抑制剂（BSJ-04-175）和损灭剂（BSJ-04-146），以评估在癌症模型中全部消除所有FAK活性的后果和优点。BSJ-04-146可以迅速且有效地在癌细胞中高度特异性地获得蛋白质组范围内的FAK降解，并在小鼠体内引起持久的降解。与激酶抑制相比，对FAK定向降解在下游信号和癌细胞的存活和迁移上表现出明显的改善活性。总之，BSJ-04-175和BSJ-04-146是用于通过小分子抑制或降解FAK来剖析其特定后果的有价值的化学工具。©2023 Wiley-VCH GmbH。

Focal adhesion kinase (FAK) is an attractive drug target due to its overexpression in cancer. FAK functions as a non-receptor tyrosine kinase and scaffolding protein, coordinating several downstream signaling effectors and cellular processes. While drug discovery efforts have largely focused on targeting FAK kinase activity, FAK inhibitors have failed to show efficacy as single agents in clinical trials. Here, using structure-guided design, we report the development of a selective FAK inhibitor (BSJ-04-175) and degrader (BSJ-04-146) to evaluate the consequences and advantages of abolishing all FAK activity in cancer models. BSJ-04-146 achieves rapid and potent FAK degradation with high proteome-wide specificity in cancer cells and induces durable degradation in mice. Compared to kinase inhibition, targeted degradation of FAK exhibits pronounced improved activity on downstream signaling and cancer cell viability and migration. Together, BSJ-04-175 and BSJ-04-146 are valuable chemical tools to dissect the specific consequences of targeting FAK through small molecule inhibition or degradation.© 2023 Wiley-VCH GmbH.