Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development

Abstract

The p53 tumor suppressor is a potent transcription factor that plays a key role in the regulation of cellular responses to stress. It is controlled by its negative regulator MDM2, which binds directly to p53 and inhibits its transcriptional activity. MDM2 also targets p53 for degradation by the proteasome. Many tumors produce high levels of MDM2, thereby impairing p53 function. Restoration of p53 activity by inhibiting the p53-MDM2 interaction may represent a novel approach to cancer treatment. RG7112 (2g) is the first clinical small-molecule MDM2 inhibitor designed to occupy the p53-binding pocket of MDM2. In cancer cells expressing wild-type p53, RG7112 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenografts.

Keywords: MDM2; RG7112; cancer; p53; protein−protein interaction.

Figure 1

Early lead compound Nutlin-3a and RG7112.

Figure 2

New imidazoline analogues.

Scheme 1. Synthesis of RG7112 (2g)

Reagents and conditions: (a) AlMe₃, toluene, reflux; (b) phosgene, triethylamine; (c) compound 7, triethylamine; (d) chiral separation

Figure 3

Crystal structure of MDM2 bound to compound 2g (carbon atoms drawn in yellow, nitrogen in blue, oxygen in red, chlorine in green, and sulfur in orange). PDB code: 4IPF.

Figure 4

Overlay of the crystal structures of MDM2 bound to compound 2g (green) and compound 1 (Nutlin-3a, gold; PDB code: 4J3E).