p53 is the most frequently mutated target in human cancer, with mutations found in >50% of all tumors that have a deleterious effect on it and other related tumor suppressors. This cancer susceptibility gene is the subject of significant pharmacological interest, with most effort focused on developing reactivators of mutant p53 in cancers. Comparatively less studied is the aggregation and misfolding of mutp53 protein. Mutations in p53 result in the aggregation of the protein, which can itself acquire oncogenic GOF along with sequestering functional wt p53 and other tumor suppressors (e.g., p63 and p73).
Using TREVENTIS technologies we have identified several classes of drug-like compounds that inhibit mutP53 oligomerization in a dose-dependent manner. Our preliminary results in cells demonstrated that half of those hits inhibited cell growth of mutant p53 cells, but little toxicity on wt cells. We are moving these compounds forward to further discovery efforts in this exciting new area. In 2023, Treventis received a grant of $489,738 from the U.S. Department of Defense to further explore anti-mutP53 targeting small molecules.