HLI373 dihydrochloride is a potent Hdm2 inhibitor, efficiently restraining the ubiquitin ligase activity of Hdm2 and effectively prompting apoptosis in DNA-damaging agent-sensitive tumor cells[1]. Additionally, HLI373 dihydrochloride exhibits antimalarial activity[2].

HLI373 (3-15 μM; 15 hours) selectively kills tumor cells harboring wild type p53[1]. It stabilizes cellular Hdm2 in a dose-dependent manner (10-50 μM) and activates p53 transcription (3 μM)[1]. HLI373 selectively inhibits auto-ubiquitylation of Hdm2[1]. Co-transfection with plasmids encoding p53 and Hdm2 results in degradation of p53, which is blocked by HLI373 (5-10 μM; 8 hours). The compound increases p53 and Hdm2 protein levels in cells and demonstrates lower IC50 values (below 6 μM) against chloroquine-sensitive P. falciparum D6 strain (PfD6) and chloroquine-resistant P. falciparum W2 strain (PfW2), exhibiting early growth inhibition[2]. HLI373 is an MDM2 inhibitor that interrupts its ubiquitin E3 ligase activity, affecting the ubiquitylation of its substrate protein p53 by targeting the C-terminus functioning as an E3 ubiquitin ligase[3].

Cell Viability Assay[1]

Cell Line: Wild type p53 mouse embryo fibroblasts (MEFs), and p53-deficient MEFs.