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

  • J Med Chem. 2024 Jul 11;67(13):10622-10642. doi: 10.1021/acs.jmedchem.4c00080.
Song Liu  1 ,  Jing Sui  1 ,  Baozhu Luo  1 ,  Jiangnan Zhang  1 ,  Xinrong Xiang  1 ,  Tao Yang  1  2 ,  Youfu Luo  1 ,  Jie Liu  1
Affiliations
  • 1. Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2. Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
PMID: 38905539 DOI: 10.1021/acs.jmedchem.4c00080
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. 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.