Discovery of 5-(Piperidin-4-yl)-1,2,4-oxadiazole Derivatives as a New Class of Human Caseinolytic Protease P Agonists for the Treatment of Hepatocellular Carcinoma

Abstract

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. <i>Org. Biomol. Chem</i>. 2009, 7 (21), 4337-4348). Compound <b>SL44</b> 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, <b>SL44</b> induces degradation of respiratory chain complex subunits and leads to apoptosis in HCC cells. <i>In vivo</i> results demonstrated that <b>SL44</b> 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.