Abstract
Loss of the normal tumor suppressive functions of p53, the "guardian of the genome," is common in advanced cancers. Mutations in TP53 occur in various ways which can result in p53 null tumor cells as well as in tumor cells highly expressing missense, gain of oncogenic function p53 proteins. Gain of function p53 proteins not only lose wild type p53 pro-apoptotic and DNA repair functions, but gain novel oncogenic functions. We hypothesize that directly targeting missense mutant p53 instead of downstream pathways has substantial advantages. Analogues of curcumin have been reported to bind mutant p53 to accomplish this goal. In this report, we developed a series of novel molecules derived from the curcumin backbone. We identified a particularly active curcumin analogue, AKT-100, and demonstrate binding to mutant p53 proteins to reinstate p53 wild type functionality. This agent exhibits impressive cell killing in multiple ovarian and serous endometrial cancer cells at concentrations ranging from 100-300 nM. AKT-100 is also synergistic with the PARP inhibitor olaparib and with chemotherapy by inhibiting alternative DNA repair mechanisms associated with resistance to standard therapies. RNA sequencing confirms that AKT-100 reactivates wild type p53-driven expression of genes associated with normal cell cycle regulation (induction of CDKN1A encoding p21 and GADD45A ), apoptosis (induction of PMAIP1 encoding Noxa and DR5 encoding Death Receptor 5), and inhibits DNA replication and repair in cancer cells. Thus, p53 reactivators under development, such as AKT-100, hold promise as novel therapeutic agents to directly target missense mutant, gain of oncogenic function p53.