Abstract
The p53 and nuclear factor κB (NF-κB) pathways play crucial roles in human cancer development. Simultaneous targeting of both pathways is an attractive therapeutic strategy against cancer. In this study, we report an antitumor molecule that bears a pyrrolo[3,4-c]pyrazole scaffold and functions as an enantiomeric inhibitor against both the p53-MDM2 interaction and the NF-κB activation. It is a first-in-class enantiomeric inhibitor with dual efficacy for cancer therapy. Synergistic effect was observed in vitro and in vivo. Docking and molecular dynamics simulation studies further provided insights into the nature of stereoselectivity.
Highlights
The p53 tumor suppressor protein is believed to play a crucial role in preventing cancer development by regulating cell cycle and inducing apoptosis [1]
Similar behaviour for IκBα with no differences was observed when treated with the other enantiomer, indicating that the compound S-5s of pyrrolo[3,4-c]pyrazole compound suppressed nuclear factor κB (NF-κB) activation through inhibition of IκBα phosphorylation mediated by the IKKs phosphorylation
The similar but much weaker effect of the other R-5s was probably induced by the p53 pathway rather than by direct inhibition of the NF-κB pathway
Summary
The p53 tumor suppressor protein is believed to play a crucial role in preventing cancer development by regulating cell cycle and inducing apoptosis [1]. MDM2 protein is a negative regulator of the p53 pathway and its overexpression in cancer cells may lead to inactivation of p53 cellular function. The NF-κB complex responsible for regulating the transcription of DNA is suppressed by a family of inhibitors called IκBs in the cytoplasm via protein association. The IκB inhibitory proteins are phosphorylated by IκB kinase (IKK) composed of α, β and γ subunits, resulting in ubiquitination and eventual degradation of the IκBs. The dissociated NF-κB complex subsequently enters the nucleus where it binds to DNA and activates gene expression. Inhibition of NF-κB signalling by preventing the IKK phosphorylation of IκB proteins has potential therapeutic applications to the treatment of cancer and inflammatory diseases [10]
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