Cancer therapeutic approach based on conformational stabilization of mutant p53 protein by small peptides

Oncotarget, 2016 Mar 15;7(11):11817-37

Perry Tal, Shay Eizenberger, Elad Cohen, Naomi Goldfinger, Shmuel Pietrokovski, Moshe Oren and Varda Rotter


The p53 tumor suppressor serves as a major barrier against malignant
transformation. Over 50% of tumors inactivate p53 by point mutations in its DNA
binding domain. Most mutations destabilize p53 protein folding, causing its partial
denaturation at physiological temperature. Thus a high proportion of human tumors
overexpress a potential potent tumor suppressor in a non-functional, misfolded
form. The equilibrium between the properly folded and misfolded states of p53 may
be affected by molecules that interact with p53, stabilizing its native folding and
restoring wild type p53 activity to cancer cells. To select for mutant p53 (mutp53)
reactivating peptides, we adopted the phage display technology, allowing interactions
between mutp53 and random peptide libraries presented on phages and enriching for
phage that favor the correctly folded p53 conformation. We obtained a large database
of potential reactivating peptides. Lead peptides were synthesized and analyzed for
their ability to restore proper p53 folding and activity. Remarkably, many enriched
peptides corresponded to known p53-binding proteins, including RAD9. Importantly,
lead peptides elicited dramatic regression of aggressive tumors in mouse xenograft
models. Such peptides might serve as novel agents for human cancer therapy.