Recent Progress and Clinical Development of Inhibitors that Block MDM4/p53 Protein–Protein Interactions

Abstract

MDM4 is a homologue of MDM2, serving cooperatively as the negative regulator of tumor suppressor p53. Under the shadow of MDM2 inhibitors, limited efforts had been put into the discovery of MDM4 modulators. Recent studies of the experimental drug ALRN-6924, a dual MDM4 and MDM2 inhibitor, suggest that concurrent inhibition of MDM4 and MDM2 might be beneficial over only MDM2 inhibition. In view of the present research progress, we summarized published inhibitors of MDM4/p53 interactions including both peptide-based compounds and small molecules. Cocrystal structures of ligand/ MDM4 complexes have been examined, and their structural features were compiled and compared in order to show the molecular basis required for high MDM4 binding affinities. Representative examples of small-molecule MDM4 inhibitors were discussed, followed by clinical results of ALRN-6924, together, providing a consolidated reference for further development of MDM4 inhibitors, either dual or selective.

The Correlation of Mouse Double Minute 4 (MDM4) Polymorphisms (rs4245739, rs1563828, rs11801299, rs10900598, and rs1380576) with Cancer Susceptibility: A Meta-Analysis

“…As a negative regulator of the P53 protein, MDM4 can downregulate P53 activity and lead to cancer. Meanwhile, MDM4 has been investigated extensively as a target spot for targeted malignancy therapy [ 38 ]. Single-nucleotide polymorphisms in the MDM4 gene can impact the MDM4 activity and hence tumor susceptibility and prognosis.…”

Molecular glues modulate protein functions by inducing protein aggregation: A promising therapeutic strategy of small molecules for disease treatment

“…Murine double minute 2 (MDM2) and MDMX, the negative regulator of the P53 tumor suppressor, are promising targets for cancer therapy 43 . MDM2 antagonists alone may cause tumor cells to overexpress MDMX to inhibit the P53 pathway, therefore, the identification of MDM2/MDMX dual antagonists has been intensively studied recently 44 , 45 .…”

Combination strategies to promote sensitivity to cytarabine-induced replication stress in acute myeloid leukemia with and without DNMT3A mutations

“…Interest in compounds that impede p53 binding to MDM2 and/or MDMX and thus restore p53 activity has led to an explosion of small molecule drug candidates, as well as stapled peptides and PROteolysis TArgeting Chimeras (PROTACs) (90)(91)(92)(93)(94). Additionally, taking aim at negative regulators of the p53 downstream effectors, such as BCL-2…”