The mitochondrial caseinolytic protease P (ClpP) is a target candidate for treating leukemia; however, the effects of ClpP modulation on solid tumors have not been adequately explored. Here, we report a potent activator of ClpP with the therapeutic potential for pancreatic ductal adenocarcinoma (PDAC). We first validated that aberrant ClpP activation leads to growth arrest of PDAC cells and tumors. We then performed high-throughput screening and synthetic optimization, from which we identified ZG111, a potent activator of ClpP. ZG111 binds to ClpP and promotes the ClpP-mediated degradation of respiratory chain complexes. This degradation activates the JNK/c-Jun pathway, induces the endoplasmic reticulum stress response, and consequently causes the growth arrest of PDAC cells. ZG111 also produces inhibitory effects on tumor growth in cell line-derived and patient-derived xenograft mouse models. Altogether, our data demonstrate a promising therapeutic strategy for PDAC suppression through the chemical activation of ClpP.

线粒体酪蛋白分解酶 P (ClpP) 是治疗白血病的候选靶标；然而，ClpP 调节对实体瘤的影响尚未得到充分探索。在这里，我们报道了一种有效的 ClpP 激活剂，具有治疗胰腺导管腺癌 (PDAC) 的潜力。我们首先验证了 ClpP 的异常激活会导致 PDAC 细胞和肿瘤的生长停滞。然后我们进行了高通量筛选和合成优化，从中我们鉴定出了 ZG111，一种有效的 ClpP 激活剂。 ZG111 与 ClpP 结合并促进 ClpP 介导的呼吸链复合物降解。这种降解激活 JNK/c-Jun 通路，诱导内质网应激反应，从而导致 PDAC 细胞生长停滞。 ZG111 还对细胞系来源和患者来源的异种移植小鼠模型中的肿瘤生长产生抑制作用。总而言之，我们的数据证明了通过化学激活 ClpP 抑制 PDAC 的一种有前景的治疗策略。