Optimizing the oxazoloisoindolinone family: Identification and biological evaluation of a potent and selective indole-based p53 activator in human colorectal cancer

With 1.8 million new cases in 2018, colorectal cancer (CRC) is considered one of the most deadliest cancers due to its frequency and high rate of mortality. The molecular pathogenesis of CRC involves, in 40-50 % of cases, the mutation of protein p53. This long-established tumor suppressor is inactivated in all human cancers, either by protein-protein interaction with its main inhibitors MDM2/X or by hotspot mutation. Unfortunately, patients with mutated p53 gene are likely to develop multidrug resistance, which can lead to therapeutic failure. Our research group is actively involved in the identification of new p53 modulators. In this work we want to share our latest results in the identification of compound 1, an optimized (R)-tryptophanol-derived oxazoloisoindolinone that was found to be six-fold more active than our hit compound SLMP53-1 in colon carcinoma HCT116 cell line. Interestingly, in vitro results showed that compound 1 has increased selectivity for HCT116 cells with p53, and has low toxicity in normal cells. Molecular docking simulations and binding assays, reported in this study, were used to give important insights about why this novel enantiopure oxazoloisoindolinone analogue cannot be considered an MDM2 inhibitor.