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

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.