The p53 protein, also known as the “guardian of the genome”, has an important role in the tumor suppression and regulation of cell processes. The majority of human cancers show inactivation of the p53 pathway. This perturbation can occur either by negative regulation, either by mutation or deletion of its gene. In tumors harboring wt p53, the MDM2 and MDMX homologous proteins are the main contributors for suppressing the p53 functions. In the last years, the development of p53-MDM2 PPI small molecule inhibitors has been one of the most popular approaches to reactivate wt p53, with eight clinical candidates under evaluation. However, it is now considered that, to achieve a full p53 reactivation, a dual inhibition of MDM2 and MDMX is required. Until today, there is no dual small molecule inhibitors of p53-MDM2/X PPIs in clinical trials.
In the last years, our group has been working on the design of five-membered spirooxindoles to develop novel anticancer agents. This work explores the design of the spiropyrazoline oxindole family to act as MDM2/X dual inhibitors. Here, we report an in silico-guided design, synthetic optimization, and biological evaluation of two libraries of spiropyrazoline oxindoles.
p53 also interacts with CREBBP. The inhibition of the p53-CREBBP PPI in certain biological circumstances can result in the p53 stabilization. For this purpose, PROTAC technology that allows to degrade the CREBBP protein was implemented, based on a lead CREBBP ligand developed in the Conway group.
Also, a yeast target-based screening of enantiopure tryptophanol derivatives led to the identification of dual p53-MDM2/X inhibitors, which were further optimized to compounds DIMP53-1, SYNAP and SLMP53-1, the last being also a mut p53 reactivator. To better understand the mechanism of action of this chemical family, in particular of SLMP53-1, two types of chemical probes were prepared, and preliminary in vitro cell assays were performed to evaluate their potential in future applications. Also, the preliminary biological and photocrosslinking results for SLMP53-1 photoaffinity-based probe showed its potential for the biological target profile of this compound.
Overall, this PhD thesis has provided valuable insights in the development of p53 activators
