30 research outputs found
Novel allosteric mechanism of p53 activation by small molecules for targeted anticancer therapy
Given the immense significance of p53 restoration for anti-cancer therapy and that p53-activating molecules are in clinical trials, elucidation of the mechanisms of action of p53-activating molecules is of the utmost importance. Here we report a discovery of a novel allosteric modulation of p53 by small molecules, which is an unexpected turn in the p53 story. We identified a structural element involved in allosteric regulation of p53, whose targeting by small molecules RITA, PpIX and licofelone blocks the binding of two p53 inhibitors, MDM2 and MDMX, thereby restoring p53 function. Deletion and mutation analysis followed by molecular modeling and its thorough validation, identified the key p53 residues S33 and S37 targeted by RITA and PpIX. We propose that the binding of small molecules to the identified site in p53 induces a conformational trap preventing p53 from the interaction with MDM2 and MDMX. These results point to a high potential of allosteric activators as targeted drugs. Our study provides a basis for the development of therapeutics with a novel mechanism of action, thus extending the p53 pharmacopeia
ROS-dependent activation of JNK converts p53 into an efficient inhibitor of oncogenes leading to robust apoptosis
TP53 mutations emerge with HDM2 inhibitor SAR405838 treatment in de-differentiated liposarcoma
Parallel G-Quadruplex-Specific Fluorescent Probe for Monitoring DNA Structural Changes and Label-Free Detection of Potassium Ion
HPV-negative penile squamous cell carcinoma: disruptive mutations in the TP53 gene are common
Anticancer Agents: Does a Phosphonium Behave Like a Gold(I) Phosphine Complex? Let a “Smart” Probe Answer!
Integrated high-throughput analysis identifies Sp1 as a crucial determinant of p53-mediated apoptosis
Gold–phosphine–porphyrin as potential metal-based theranostics
Two new gold-phosphine-porphyrin derivatives were synthesized and fully characterized, and their photophysical properties investigated along a water-soluble analog. The cytotoxicity of the compounds was tested on cancer cells (HCT116 and SW480), and their cell uptake was followed by fluorescence microscopy in vitro (on SW480). The proof that the water-soluble gold-phosphine-porphyrin is a biologically active compound that can be tracked in vitro was clearly established, especially concerning the water-soluble analog. Some preliminary photodynamic therapy (PDT) experiments were also performed. They highlight a dramatic increase of the cytotoxicity when the cells were illuminated for 30 min with white light