HLI373 is an Efficacious Hdm2 Inhibitor, with Antimalarial Activity
Posted On 2020-07-04
Hdm2 is an ubiquitin-protein ligase. Hdm2 suppresses the transcriptional activity of the tumor suppressor p53 and promotes its degradation. HLI373 is an efficacious Hdm2 inhibitor.
HLI373 is effective in inducing apoptosis of several tumor cell lines that are sensitive to DNA-damaging agents. These results suggest that HLI373 could serve as a potential lead for developing cancer therapeutics based on inhibition of the ubiquitin ligase activity of Hdm2. HLI373 is highly soluble in aqueous solution and substantially more potent than the HLI98s inactivating p53 and killing transformed cells. Moreover, HLI373 is effective in inducing apoptosis of several tumor cells that are sensitive to DNA-damaging agents. In addition, HLI373 increases p53 and Hdm2 protein levels in cells.
HLI373 also inhibits auto-ubiquitylation of bacterially-expressed Hdm2 in a cell-free ubiquitylation assay system. HLI373 increases p53 in cells through inhibiting Hdm2-mediated ubiquitylation and selectively inhibits the auto-ubiquitylation of Hdm2. In particular, HLI373 stabilizes cellular Hdm2 in a dose-dependent manner and inhibits degradation and ubiquitylation of p53 and Hdm2. HLI373 induces a dose-dependent increase in luciferase activity and demonstrates substantially greater potency than the HLI98s.
Induction of selective apoptosis of transformed cells and MEFs harboring wild type p53 by HLI373. HLI373 also increases PARP cleavage in C8 cells but not A9 cells, consistent with HLI373 inducing apoptotic cell death as a consequence of p53 activation. Furthermore, HLI373 kills tumor cells in a p53-dependent manner and represents a potential lead for the development of cancer therapeutics. HLI373 selectively kills tumor cells harboring wild type p53. Taken together, HLI373 is a potentially drug-able compound that serves as a potential lead for therapeutics targeting the E3 activity of Hdm2.
Jirouta Kitagaki, et al. Targeting Tumor Cells Expressing p53 With a Water-Soluble Inhibitor of Hdm2. Mol Cancer Ther. 2008 Aug;7(8):2445-54.