Targeting mutant p53 with tryptophanol-derived small molecules

Previously, our group developed tryptophanol‐derived hits that have p53-dependent anti-proliferative activity in wild-type expressing human cancer cells, and also in mutant p53-expressing human cancer cells. These hit compounds are nongenotoxic, have low cytotoxicity against normal cells, and display antitumor activity in xenograft mouse models, representing new mutp53-reactivating agents with a distinct mechanism of action from those currently reported.

In this project, we intend to study in more detail this chemical family, with the aim of obtaining novel mutant p53 reactivators with improved drug-like properties. We want to understand why small modifications in the hit leads to derivatives that reactivate different p53 mutants, using molecular dynamics and docking. Based on these in silico studies, a hit-to-lead optimization of tryptophanol-derived small molecules will be carried, to improve solubility, potency and selectivity for cancer cells harboring mutated p53. To confirm the reactivation of the tumor suppressor p53 function of mutated p53, we will use binding and 2D cell assays. The most promising compounds will be also evaluated in more complex 3D cellular models and ex-vivo. Additionally, we will synthesize potential metabolites of the hit compounds, as well as two types of chemical probes. The biological evaluation of the metabolites will provide insights into the potential side-effects associated to this scaffold. The probes based on the hit compounds will be valuable chemical tools for target elucidation.