Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials

Abstract

Abstractp53, encoded by the tumor suppressor gene TP53, is one of the most important tumor suppressor factors in vivo and can be negatively regulated by MDM2 through p53–MDM2 negative feedback loop. Abnormal p53 can be observed in almost all tumors, mainly including p53 mutation and functional inactivation. Blocking MDM2 to restore p53 function is a hotspot in the development of anticancer candidates. Till now, nine MDM2 inhibitors with different structural types have entered clinical trials. However, no MDM2 inhibitor has been approved for clinical application. This review focused on the discovery, structural modification, preclinical and clinical research of the above compounds from the perspective of medicinal chemistry. Based on this, the possible defects in MDM2 inhibitors in clinical development were analyzed to suggest that the multitarget strategy or targeted degradation strategy based on MDM2 has the potential to reduce the dose-dependent hematological toxicity of MDM2 inhibitors and improve their anti-tumor activity, providing certain guidance for the development of agents targeting the p53–MDM2 interaction.

Targeting Apoptosis in AML: Where Do We Stand?

“…Interestingly, ALRN-6924 does not induce deep levels of apoptosis in healthy tissues, even at the highest doses tested; however, it can induce reversible cell cycle arrest in properly proliferating cells. This concept, called cyclotherapy, offers the chance to selectively protect tissues, such as bone marrow, from cytotoxic chemotherapeutics, thus enabling cancer treatment with fewer side effects [ 128 , 132 ].…”

Transcription Factors and Cancer

“…Targeting the p53/MDM2 interaction is correspondingly enticing, and investment in the development of such therapeutics has translated into 9 inhibitors currently under investigation in clinical trials. These inhibitors generally target the deep hydrophobic cavity where 3 p53 amino acid residues, Phe19, Trp23, and Leu26, interact with MDM2 78 …”

“…Although inhibiting MDM2 is a viable therapeutic strategy for cancers with wild-type p53, the remaining 50% of cancers are hindered by p53 mutations; this illustrates a prominent limitation of this approach 78 . Moreover, MDMX, a homolog of MDM2, has been shown to stabilize MDM2, and formations of MDM2/MDMX dimers augment p53 ubiquitination 76,86–88 .…”

Drug sensitivity profiling of 3D tumor tissue cultures in the pediatric precision oncology program INFORM

“…However, tumors with inactivating mutations in TP53 are resistant to most MDM2 inhibitors (reviewed in refs. [21][22][23] ). To determine whether this correlation was reflected in our DSP results, we visualized MDM2 inhibitor (idasanutlin and AMG-232) sensitivity (determined as DSS asym quantiles) and the TP53 status of our DSP samples in an unsupervised hierarchical clustering heatmap.…”