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Yang, Y. et al. Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells. Cancer Cell 7, 547-559

Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute at Frederick, NIH, 1050 Boyles Street, Frederick, MD 21702, USA.
Cancer Cell (Impact Factor: 23.89). 07/2005; 7(6):547-59. DOI: 10.1016/j.ccr.2005.04.029
Source: PubMed

ABSTRACT The p53 tumor suppressor protein is regulated by its interaction with HDM2, which serves as a ubiquitin ligase (E3) to target p53 for degradation. We have identified a family of small molecules (HLI98) that inhibits HDM2's E3 activity. These compounds show some specificity for HDM2 in vitro, although at higher concentrations effects on unrelated RING and HECT domain E3s are detectable, which could be due, at least in part, to effects on E2-ubiquitin thiol-ester levels. In cells, the compounds allow the stabilization of p53 and HDM2 and activation of p53-dependent transcription and apoptosis, although other p53-independent toxicity was also observed.

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    • "On account of the importance of the p53-MDM2/ MDMX pathway in the initiation and development of wild-type p53- containing tumors, intensive studies over the past decade have been aiming to identify small molecules that could specifically target individual protein molecules of this pathway for developing a better moleculetargeting anticancer therapy [25]. Several small molecules or peptides have been reported to activate p53 by either blocking its binding to MDM2 [26] [27] [28], inhibiting MDM2 E3 ubiquitin ligase activity [29], or inhibiting MDMX-p53 binding [30]. Activating p53 by targeting its deacetylase(s) is another new strategy. "
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    • "Accordingly, smallmolecule MDM2 inhibitors have been developed that specifically target the E3 ligase activity of MDM2 (Yang et al, 2005). HLI98 represents a small-molecule MDM2 inhibitor of the first generation that blocks the E3 ligase activity of MDM2 leading to stabilization of p53, p53-dependent transcription and induction of cell death (Di et al, 2011; Yang et al, 2005). A structural study confirmed the mode of action of small-molecule MDM2 antagonists nutlins showing that these compounds bind MDM2 via the p53-binding pocket, thereby preventing its interaction with p53 (Vassilev et al, 2004). "
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    • "All these data suggest that the observed effects of HBX 19,818 are likely the result of USP7 targeting. Most attempts to target Mdm2 have focused on the identification of small molecules, such as the nutlins, which prevent its interaction with p53 (Vassilev et al., 2004), or on inhibiting its E3 ligase activity (Yang et al., 2005). We adopted an alternative approach based on the identification of small-molecule inhibitors of USP7; an ubiquitin-specific protease required for Mdm2-dependent p53 destabilization. "
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