Abstract
p53 is the major tumor suppressor and the most frequently inactivated gene in cancer. p53 could be disabled either by mutations or by upstream negative regulators, including, but not limited to MDM2 and MDMX. p53 activity is required for the prevention as well as for the eradication of cancers. Restoration of p53 activity in mouse models leads to the suppression of established tumors of different origin. These findings provide a strong support to the anti-cancer strategy aimed for p53 reactivation. In this review, we summarize recent progress in the development of small molecules, which restore the tumor suppressor function of wild-type p53 and discuss their clinical advance. We discuss different aspects of p53-mediated response, which contribute to suppression of tumors, including non-canonical p53 activities, such as regulation of immune response. While targeting p53 inhibitors is a very promising approach, there are certain limitations and concerns that the intensive research and clinical evaluation of compounds will hopefully help to overcome.
Highlights
Since p53 discovery 40 years ago, it has been established that p53 is a transcriptional factor, which binds to the promoters of its target genes in a sequence-specific manner and regulates their expression, thereby controlling cell cycle and cell death
Concomitant inhibition of MDM2 and BCL-xL or Bcl-2 demonstrated significant synergy in p53 wild-type cell lines in vitro (Carter et al, 2015; Chapeau et al, 2017). Another therapeutic option could be provided by a combination of RG7112 with TNF-related apoptosis inducing ligand (TRAIL) agonist rhTRAIL (Urso et al, 2017)
Concluding remarks A number of ongoing clinical trials are using p53-reactivating compounds in combination with different chemotherapeutic drugs, so we might get some clues for patient stratification from these clinical studies
Summary
Since p53 discovery 40 years ago, it has been established that p53 is a transcriptional factor, which binds to the promoters of its target genes in a sequence-specific manner and regulates their expression, thereby controlling cell cycle and cell death. In silico screening identified lithocolic acid (LCA), a steroid fatty acid present in bile, as MDMX inhibitor with higher preference over MDM2 It induces apoptosis in HCT116 human cells, predominantly in p53-dependent manner. Mentioned stapled peptide SAH-p53-8 exhibited a high affinity to MDMX, with a 25-fold binding preference for MDMX over MDM2 (Bernal et al, 2010) Another highly selective and dual target stapled peptide, ATSP-7041, displayed a robust p53-dependent tumor growth suppression in xenograft cancer models with MDM2/MDMX overexpression (Chang et al, 2013). Several non-genotoxic DNA-intercalating compounds and/or RNA PolI/II inhibitors promote the release of ribosomal proteins, leading to p53 activation and cancer cell elimination Examples of this kind of compounds are cyclin-dependent kinase (CDK) inhibitor roscovitine (David-Pfeuty et al, 2001), actinomycin D (Choong et al, 2009), BMH-21 (Peltonen et al, 2014), and CX5461 (Bywater et al, 2012). Deubiquitinase USP7 ( known as HAUSP) plays a critical role counteracting p53 and MDM2 degradation, making it an interesting target for the development of inhibitors
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