The tumor protein p53 is a pivotal tumor suppressor protein and a mainstay of the body’s cellular anti-cancer defense system. As a potent transcription factor, TP53 regulates multiple downstream target genes implicated in cell-cycle control, apoptosis, senescence, and DNA repair. In particular, tumor protein p53 (TP53) is one of the most frequently mutated genes in cancer. Moreover, MDM2, an E3 ligase, regulates TP53 function, and protein stability by three main mechanisms. First, MDM2 binds to the transactivation domain of TP53 and represses the transcriptional activity of TP53. Second, MDM2 transports the transcription factor TP53 from the nucleus to the cytoplasm, and third, the E3 ligase function of MDM2 facilitates proteasome-mediated TP53 protein degradation.

MDM2 and p53 form a negative-feedback loop, in which p53 induces the expression of MDM2, which in turn promotes the degradation of p53 and quenches cellular p53 activity. Especially, MDM2-p53 interaction is a major target for cancer therapy. In particular, several MDM2-p53 protein-protein interaction inhibitors are currently being evaluated in clinical development. Therefore, Andreas Gollner, et al started investigations to identify a highly potent MDM2 inhibitor capable of achieving efficacy with less frequent dosing in mice. Herein researchers report the discovery of an MDM2-p53 protein-protein interaction inhibitor. Importantly, BI-0252 acts as an MDM2-p53 inhibitor with an IC50 of 4 nM. Besides, BI-0252 leads to time-dependent mRNA induction of TP53 target genes including CDKN1a, MDM2, and BBC3.

All in all, BI-0252 is an orally active inhibitor of the MDM2-p53 interaction for the treatment of cancer.

Gollner A, et al. Discovery of Novel Spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one Compounds as Chemically Stable and Orally Active Inhibitors of the MDM2-p53 Interaction. J Med Chem. 2016 Nov 23;59(22):10147-10162.