Fig. 2.

Mechanisms of action for drugs that target wild-type p53—a number of compounds now exist that serve to enhance the function of wild-type p53 by increasing the stability of p53 through various mechanisms: The largest group (nutlins, benzodiazepinediones and spiro-oxindoles) serve to increase the stability of p53 by targeting the MDM2:p53 interaction. This leads to decreased MDM2 mediated proteasomal degradation of p53. MDMX inhibitors block the MDMX-p53 interaction so as to activate wild-type p53. RITA also stabilizes wild-type p53 supposedly through binding p53 and inducing a conformational change that disrupts the p53:MDM2 binding, though this is controversial. Other compounds (tenovins) enhance the stability of p53 through inhibition of the sirtuins