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InOncology.com

MDM2-p53 antagonist

BI 907828: an MDM2-p53 antagonist

BI 907828* is an oral murine double minute 2 (MDM2)-p53 antagonist that promotes p53-mediated cell cycle arrest and apoptosis.1,2  It is undergoing Phase I clinical investigation as a monotherapy in patients with wild-type TP53-enriched solid tumours.2

The roles of MDM2 and p53

MDM2 is an E3 ubiquitin ligase that has several substrates. A major substrate is p53, which is negatively regulated by MDM2, as shown in studies of MDM2-deficient mice.3,4

In non-malignant cells that are not exposed to stress signals, the auto-regulatory feedback loop between MDM2 and p53 is central in limiting aberrant activity of p53 and keeping its concentrations low.5-7 p53 can be activated in response to a wide variety of stress signals and, acting as a transcription factor, can mediate several downstream cellular responses, including cell cycle arrest and DNA repair, senescence and apoptosis.1,3

In human cancers, the TP53 gene encoding the tumour suppressor protein p53 is frequently mutated or deleted, or the function of wild-type p53 protein is inhibited by high levels of its negative regulator, MDM2. These mechanisms frequently lead to the downregulation of the p53 pathway in cancer.3

Previous studies have demonstrated that small molecule inhibitors of MDM2-p53 interaction can activate p53 in tumours with wild-type p53, thereby inducing cell cycle arrest, as well as apoptosis in tumour cells.8

About BI 907828

Mechanism of action

BI 907828 is a MDM2-p53 antagonist that blocks the interaction between MDM2 and p53 by binding to free MDM2. This prevents MDM2 from inactivating p53, which subsequently restores p53 function in tumours with wild-type p53 and induces target gene expression in processes such as cell cycle arrest and DNA repair, senescence and apoptosis.1,4

MDM2-p53 antag mechanism of action

Clinical development

BI 907828 is currently undergoing clinical investigation as a monotherapy in a Phase I trial in patients with solid tumours.2 Dose escalation is being investigated in a population enriched for wild-type TP53 tumours, and dose expansion cohorts will be enriched for wild-type TP53 and MDM2-amplified disease.2

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AE, adverse event; DCR, disease control rate; DLT, dose-limiting toxicity; MDM2, murine double minute 2; MTD, maximum tolerated dose; ORR, objective response rate; PFS, progression-free survival; PK/PD, pharmacokinetics/pharmacodynamics.

References

1

Boehringer Ingelheim. Data on file.

2

ClinicalTrials.gov. NCT03449381. https://clinicaltrials.gov/ct2/show/NCT03449381 (Accessed: September 2018).

3

Zhao Y, et al. Acta Biochim Biophys Sin (Shanghai) 2014;46(3):180–9.

4

Montes de Octa Luna R, et al. Nature 1995;378(6553):203–6.

5

Ringhausen I, et al. Cancer Cell 2006;10(6):501–14.

6

Nag S, et al. J Biomed Res 2013;27(4):254–71.

7

Landré V, et al. Oncotarget 2014;5(18):7988–8013.

8

Shangary S, et al. Proc Natl Acad Sci USA 2008;105(10):3933–8.

9

Rudolph D, et al. AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL, USA. Abstract 4868 and poster.

10

Rinnenthal J, et al. AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL, USA. Abstract 4865 and poster.

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*This is an investigational compound and has not been approved. Its safety and efficacy have not been established.

 

© 2018 Boehringer Ingelheim International GmbH. All rights reserved.

 

Last updated: October 2018