HLI373 is an efficacious Hdm2 inhibitor, an ubiquitin ligase (E3), effective in inducing apoptosis of several tumor cells sensitive to DNA-damaging agents [1], and also shows prominent antimalarial activity [2].

HLI373, at concentrations ranging from 3-15 μM over 15 hours, preferentially induces cell death in tumor cells harboring wild type p53, according to study [1]. At higher doses (10-50 μM), it dose-dependently stabilizes Hdm2, while a lower concentration of 3 μM activates p53 transcription. This compound effectively blocks the auto-ubiquitylation of Hdm2 and, when cells are co-transfected with p53 and Hdm2, HLI373 can prevent the degradation of p53, especially at 5-10 μM after 8 hours of treatment. Moreover, it increases both p53 and Hdm2 protein levels in cells. Notably, HLI373 demonstrates potent activity against both chloroquine-sensitive and resistant strains of P. falciparum, displaying IC50 values below 6 μM and inducing early growth inhibition. Functioning as an MDM2 inhibitor by targeting its C-terminus, HLI373 disrupts the ubiquitin E3 ligase activity of MDM2, which is key to the ubiquitylation of p53, highlighting its potential in cancer therapy. In cell viability assays, it was shown to cause increased cell death in wild type p53 mouse embryo fibroblasts (MEFs) in a dose-dependent manner, whereas p53-deficient MEFs exhibited resistance. Western blot analyses revealed that the compound prevents p53 degradation in U2OS cells when co-transfected with p53 and Hdm2 encoding plasmids.