Novel allosteric mechanism of p53 activation by small molecules for targeted anticancer therapy

Abstract

Given the immense significance of p53 restoration for anti-cancer therapy, elucidation of the mechanisms of action of p53-activating molecules is of the utmost importance. Here we report a discovery of novel allosteric modulation of p53 by small molecules, which is an unexpected turn in the p53 story. We identified a structural element involved in p53 regulation, whose targeting by RITA, PpIX and licofelone block the binding of p53 inhibitors, MDM2 and MDMX. Deletion and mutation analysis followed by molecular modeling, 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 induces a conformational trap preventing p53 from the interaction with MDM2 and MDMX. These results point to a high potential of allosteric activators. Our study provides the basis for the development of therapeutics with a novel mechanism of action, thus extending the p53 pharmacological potential.

Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, induces apoptosis in TP53-deficient cancer cells

“…Small molecule protoporphyrin IX (PpIX), is a natural metabolite of δaminolevulinic acid, a pro-drug applied in clinics in photodynamic therapy of cancer (PDT) 10 . PpIX induces HeLa cells' apoptosis per se, without light excitation 11 , stabilizes and activates wild-type p53 in human colon carcinoma cells 12 and binds to p73 13 .…”