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InOncology.com

MDM2-p53 inhibitor

BI 907828* is a murine double minute 2 (MDM2)-p53 inhibitor that promotes p53-mediated cell cycle arrest and apoptosis.1 It is scheduled to undergo investigation as a monotherapy in a Phase I trial in patients with wild-type TP53 enriched solid tumours.2

About BI 907828

Mechanism of action

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

BI 907828 is a MDM2-p53 inhibitor that blocks the interaction between MDM2 and p53 by binding to free MDM2. This prevents it from inactivating p53 and leads to p53 activation in tumors with wild-type p53.

p53 signalling contributes to the regulation of multiple cellular processes, including progression through the cell cycle, DNA repair, senescence and apoptosis.1,3,4

MDM2-p53 antag mechanism of action

Figure adapted from Landre V, et al. Oncotarget 2014;5:7988-13. Reproduced under the creative Commons Licence Attribution 3.0 International (CC BY 3.0) https://creativecommons.org/licenses/by/3.0/.

The role of MDM2 and p53

MDM2 is an E3 ubiquitin ligase that has several substrates, a major one being p53, which is negatively regulated by MDM2 as shown in studies of MDM2-deficient mice.5,6

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.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 apoptosis, cell cycle arrest and DNA repair.5

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

Clinical development

BI 907828 is currently scheduled to undergo investigation in a Phase I trial in solid tumours as a monotherapy.2 The patient populations in this study will be genetically enriched. Dose escalation will take place in a population enriched for wild-type TP53 tumours, and most dose expansion cohorts will be enriched for MDM2-amplified disease.2

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AE, adverse event; DCR, disease control rate; DLT, dose-limiting toxicity; 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: April 2018.

3

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

4

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

5

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

6

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

7

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

8

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

*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: June 2018