Pf225 Azacitidine (Aza) Enhances Antileukemic Activity of the Mdm2 Inhibitor Milademetan in Tp53 Wild-Type Acute Myeloid Leukemia (Aml)

The tumor suppressor gene TP53 is one of the most frequently mutated genes in human cancer. The central role of the TP53 protein in several fundamental processes such as cancer, aging, senescence, and DNA repair has ensured enormous attention. However, the role of TP53 in acute myeloid leukemia (AML) is enigmatic. Unlike many other human cancers, a vast majority of AMLs display no genomic TP53 alterations. There is now growing appreciation of the fact that the unaltered TP53 status of tumor cells can be exploited therapeutically. As most AMLs have an intact TP53 gene, its physiological tumor‐suppressive roles could be harnessed. Therefore, the use of pharmacological activators of the TP53 pathway may provide clinical benefit in AML. Conversely, even though the frequency of TP53 mutations in AML is substantially lower than in other human cancers, TP53 mutations are associated with chemoresistance and high risk of relapse. In patients with TP53 mutations, these alterations may lead to novel, selective vulnerabilities, creating opportunities for therapeutic targeting of TP53 mutant AML. The mutational status of TP53 therefore poses challenges and opportunities in terms of advancing effective treatment strategies in AML. An increasing armamentarium of small‐molecule activators of the TP53 pathway, and a growing understanding of molecular pathways triggered by mutant TP53 have accelerated efforts aimed at targeting TP53 function in AML. In combination with standard AML chemotherapy or emerging targeted therapies, pharmacological targeting of the TP53 pathway may provide therapeutic benefit in AML.

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The role of TP53 in acute myeloid leukemia: Challenges and opportunities

Barbosa

Adams

et al. 2019

Genes Chromosomes & Cancer

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p53 as a potential target for treatment of cancer: A perspective on recent advancements in small molecules with structural insights and SAR studies

Chahat¹,

Bhatia²,

Kumar

2023

European Journal of Medicinal Chemistry

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MDM2-p53 Interaction Inhibitors: The Current State-of-Art and Updated Patent Review (2010-Present)

Rusiecki

Witkowski

Jaszczewska-Adamczak

2020

PRA

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Background: Mouse Double Minute 2 protein (MDM2) is a cellular regulator of p53 tumor suppressor (p53). Inhibition of the interaction between MDM2 and p53 proteins is a promising anticancer therapy. Objective: This updated patent review is an attempt to compile the research and achievements of the various researchers working on small molecule MDM2 inhibitors from 2010 to date. We provide an outlook into the future for therapy based on MDM2 inhibition by presenting an overview of the most relevant patents which have recently appeared in the literature. Methods: Literature and recent patents focusing on the anticancer potential of MDM2-p53 interaction inhibitors and its applications have been analyzed. We put the main emphasis on the most perspective compounds which are or were examined in clinical trials. Results: Literature data indicated that MDM2 inhibitors are therapeutically effective in specific types of cancer or non-cancer diseases. A great number of patents and research work around new MDM2- p53 interaction inhibitors, possible combinations, new indications, clinical regimens in previous years prove that this targeted therapy is in the scope of interest for many business and academic research groups. Conclusion: Novel MDM2 inhibitors thanks to higher potency and better ADME properties have shown effectiveness in preclinical and clinical development however the final improvement of therapeutic potential for MDM2 inhibitors might depend on the useful combination therapy and exploring new cancer and non-cancer indications.

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Pf225 Azacitidine (Aza) Enhances Antileukemic Activity of the Mdm2 Inhibitor Milademetan in Tp53 Wild-Type Acute Myeloid Leukemia (Aml)

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The role of TP53 in acute myeloid leukemia: Challenges and opportunities

The role of TP53 in acute myeloid leukemia: Challenges and opportunities

p53 as a potential target for treatment of cancer: A perspective on recent advancements in small molecules with structural insights and SAR studies

MDM2-p53 Interaction Inhibitors: The Current State-of-Art and Updated Patent Review (2010-Present)

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