Molecular pathways: targeting Mdm2 and Mdm4 in cancer therapy

Abstract

The p53 tumor suppressor is activated in response to cellular stresses to induce cell-cycle arrest, cellular senescence, and apoptosis. The p53 gene is inactivated by mutations in more than 50% of human tumors. In addition, tumor cells dampen p53 activities via overexpression of p53-negative regulators, in particular 2 structurally related proteins, Mdm2 and Mdm4. And yet, Mdm2 and Mdm4 possess p53-independent activities, which also contribute to tumor formation and progression. Given that Mdm2 and Mdm4 inhibit p53 activities to promote tumor development, small molecules and peptides were developed to abrogate the inhibition of p53 by Mdm proteins. Antitumor activities of these molecules have already been confirmed in preclinical studies and early-phase clinical trials. These research endeavors and clinical advances constitute the main focus of this review.

Figure 1. Schematic representation of p53-independent functions of Mdm2 and Mdm4

a. Mdm2 interacts with multiple factors to affect genomic instability, apoptosis and metastasis. hnRNP: hnRNP K protein. b. Mdm4 interacts with p21 and E2F1 to regulate cell cycle arrest and apoptosis.

Figure 2. Schematic representation of the targeting sites of Mdm protein antagonists on Mdm2, Mdm4 and p53

BDP: benzodiazepinedione; MI: MI-63/219; Stapled: SAH-p53 Stapled peptides; JNJ: JNJ-26854165; SJ: SJ-172550; p53 Binding: p53 binding domain; Acidic: Acidic domain; Zn Finger: Zn finger domain; RING: RING domain; TA: transactivation domain; PR: proline-rich domain; DNA Binding: DNA binding domain; oligo: oligomerization domain.