Chemical agonism of human caseinolytic protease P (HsClpP) is increasingly being recognized as a potential anticancer strategy due to its critical role in maintaining mitochondrial homeostasis. We unveil the discovery of 5-(piperidin-4-yl)-1,2,4-oxadiazole derivatives as a novel class of HsClpP agonists and demonstrate for the first time the application of HsClpP agonists in the treatment of hepatocellular carcinoma (HCC) (Pace, A.; Pierro, P. The new era of 1,2,4-oxadiazoles. Org. Biomol. Chem. 2009, 7 (21), 4337-4348). Compound SL44 exhibited potent HsClpP agonistic activity in the α-casein hydrolysis assay (EC₅₀ = 1.30 μM) and inhibited the proliferation of HCCLM3 cells (IC₅₀ = 3.1 μM, 21.4-fold higher than hit ADX-47273). Mechanistically, SL44 induces degradation of respiratory chain complex subunits and leads to apoptosis in HCC cells. In vivo results demonstrated that SL44 has potent tumor growth inhibitory activity and has a superior safety profile compared to the kinase inhibitor sorafenib. Overall, we developed a novel class of HsClpP agonists that can potentially be used for the treatment of HCC.

中文翻译：

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发现 5-(哌啶-4-基)-1,2,4-恶二唑衍生物作为一类新型人酪蛋白分解酶 P 激动剂用于治疗肝细胞癌


人酪蛋白分解酶 P (HsClpP) 的化学激动作用因其在维持线粒体稳态中的关键作用而日益被认为是一种潜在的抗癌策略。我们发现了 5-(哌啶-4-基)-1,2,4-恶二唑衍生物作为一类新型 HsClpP 激动剂，并首次证明了 HsClpP 激动剂在肝细胞癌 (HCC) 治疗中的应用（Pace, A.；Pierro, P. 1,2,4-恶二唑的新时代。Org. Biomol. Chem. 2009, 7 (21), 4337-4348）。化合物 SL44 在 α-酪蛋白水解测定中表现出有效的 HsClpP 激动活性 (EC ₅₀ = 1.30 μM)，并抑制 HCCLM3 细胞的增殖 (IC ₅₀ = 3.1 μM，21.4 倍)高于 ADX-47273）。从机制上讲，SL44 诱导呼吸链复合体亚基降解并导致 HCC 细胞凋亡。体内结果表明，SL44 具有有效的肿瘤生长抑制活性，并且与激酶抑制剂索拉非尼相比具有优越的安全性。总体而言，我们开发了一类新型 HsClpP 激动剂，有可能用于治疗 HCC。