The liver-specific microRNA-122*, the complementary strand of microRNA-122, acts as a tumor suppressor by modulating the p53/mouse double minute 2 homolog circuitry

Hepatology ◽  
2016 ◽  
Vol 64 (5) ◽  
pp. 1623-1636 ◽  
Author(s):  
Alina Simerzin ◽  
Elina Zorde-Khvalevsky ◽  
Mila Rivkin ◽  
Revital Adar ◽  
Jessica Zucman-Rossi ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Complementary Strand ◽  
Mouse Double Minute ◽  
Double Minute

scholarly journals Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia

2018 ◽  
Vol 10 (436) ◽  
pp. eaao3003 ◽  
Author(s):  
Luis A. Carvajal ◽  
Daniela Ben Neriah ◽  
Adrien Senecal ◽  
Lumie Benard ◽  
Victor Thiruthuvanathan ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Single Molecule ◽  
Cellular Proliferation ◽  
Wild Type ◽  
Suppressor Activity ◽  
Mouse Double Minute ◽  
Double Minute ◽  
Wild Type P53

The tumor suppressor p53 is often inactivated via its interaction with endogenous inhibitors mouse double minute 4 homolog (MDM4 or MDMX) or mouse double minute 2 homolog (MDM2), which are frequently overexpressed in patients with acute myeloid leukemia (AML) and other cancers. Pharmacological disruption of both of these interactions has long been sought after as an attractive strategy to fully restore p53-dependent tumor suppressor activity in cancers with wild-type p53. Selective targeting of this pathway has thus far been limited to MDM2-only small-molecule inhibitors, which lack affinity for MDMX. We demonstrate that dual MDMX/MDM2 inhibition with a stapled α-helical peptide (ALRN-6924), which has recently entered phase I clinical testing, produces marked antileukemic effects. ALRN-6924 robustly activates p53-dependent transcription at the single-cell and single-molecule levels and exhibits biochemical and molecular biological on-target activity in leukemia cells in vitro and in vivo. Dual MDMX/MDM2 inhibition by ALRN-6924 inhibits cellular proliferation by inducing cell cycle arrest and apoptosis in cell lines and primary AML patient cells, including leukemic stem cell–enriched populations, and disrupts functional clonogenic and serial replating capacity. Furthermore, ALRN-6924 markedly improves survival in AML xenograft models. Our study provides mechanistic insight to support further testing of ALRN-6924 as a therapeutic approach in AML and other cancers with wild-type p53.

scholarly journals Discovery, X-ray structure and CPP-conjugation enabled uptake of p53/MDM2 macrocyclic peptide inhibitors

2021 ◽  
Author(s):  
Anselm Schneider ◽  
Jörg Kallen ◽  
Johannes Ottl ◽  
Patrick C Reid ◽  
Sebastien Ripoche ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Peptide Inhibitors ◽  
Negative Regulator ◽  
Tumor Suppressor P53 ◽  
X Ray ◽  
Mouse Double Minute ◽  
Double Minute ◽  
Important Negative Regulator ◽  
Display Technique ◽  
Macrocyclic Peptide

Mouse double minute 2 homolog (MDM2, Hdm2) is an important negative regulator of the tumor suppressor p53. Using a mRNA based display technique to screen a library of >1012 in...

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

2020 ◽  
Vol 14 (4) ◽  
pp. 324-369 ◽  
Author(s):  
Rafał Rusiecki ◽  
Jakub Witkowski ◽  
Joanna Jaszczewska-Adamczak
Keyword(s):  
Therapeutic Potential ◽  
Research Work ◽  
Academic Research ◽  
Tumor Suppressor P53 ◽  
Research Groups ◽  
Current State ◽  
Mouse Double Minute ◽  
Patent Review ◽  
Main Emphasis ◽  
Double Minute

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.

scholarly journals The mouse double minute 2 309T>G polymorphism and retinoblastoma risk: A meta-analysis

2020 ◽  
Vol 34 (3) ◽  
pp. 191
Author(s):  
Jasbir Kaur ◽  
K Sooraj ◽  
Sunil Kumar ◽  
Amit Kumar ◽  
MandeepS Bajaj
Keyword(s):  
Meta Analysis ◽  
Mouse Double Minute ◽  
Double Minute

Discovery and Optimization of Chromenotriazolopyrimidines as Potent Inhibitors of the Mouse Double Minute 2−Tumor Protein 53 Protein−Protein Interaction

2009 ◽  
Vol 52 (22) ◽  
pp. 7044-7053 ◽  
Author(s):  
John G. Allen ◽  
Matthew P. Bourbeau ◽  
G. Erich Wohlhieter ◽  
Michael D. Bartberger ◽  
Klaus Michelsen ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Protein Protein Interaction ◽  
Mouse Double Minute ◽  
Double Minute

Discovery of Potent Antagonists of the Interaction between Human Double Minute 2 and Tumor Suppressor p53

2000 ◽  
Vol 43 (17) ◽  
pp. 3205-3208 ◽  
Author(s):  
Carlos García-Echeverría ◽  
Patrick Chène ◽  
Marcel J. J. Blommers ◽  
Pascal Furet
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor P53 ◽  
Double Minute

Nanopore Analysis on the Drug-Induced Conformation Change of a p53-Linker-Mouse Double Minute 2 Protein Complex

2020 ◽  
Vol 20 (1) ◽  
pp. 15-23 ◽  
Author(s):  
Hongsik Chae ◽  
Dong-Kyu Kwak ◽  
Mi-Kyung Lee ◽  
Seung-Wook Chi ◽  
Ki-Bum Kim
Keyword(s):  
Protein Complex ◽  
Conformation Change ◽  
Drug Induced ◽  
Mouse Double Minute ◽  
Double Minute
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