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BI 907828: an MDM2-p53 antagonist
BI 907828* is an oral, small molecule murine double minute 2 (MDM2)-p53 antagonist that may promote p53-mediated cell cycle arrest and apoptosis.1 It is undergoing investigation as monotherapy in a Phase I clinical involving patients with wild-type TP53-enriched solid tumours.2
The roles of MDM2 and p53
MDM2 is a negative regulator of the tumour suppressor p53.3–6 In non-malignant cells unexposed to stress signals, the auto-regulatory feedback loop between MDM2 and p53 is central to keeping its concentrations low and to limiting aberrant p53 activity.7–9
p53 can be activated in response to a wide variety of stress signals and can mediate downstream cellular responses, including cell cycle arrest, DNA repair, senescence and apoptosis.1,5 In human cancers, the TP53 gene encoding p53 is frequently mutated or deleted (or the function of wild-type p53 protein is inhibited by high MDM2 levels), leading to downregulation of the p53 pathway.5
Previous studies in patients with wild-type p53 tumours suggest that small molecule inhibitors of the MDM2-p53 interaction can activate the p53 pathway and induce cell cycle arrest and apoptosis in tumour cells.10
About BI 907828
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, thereby restoring p53 function in tumours with wild-type p53 and inducing target gene expression in processes such as cell cycle arrest and DNA repair, senescence and apoptosis.1,5,6
BI 907828’s mechanism of action
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 with TP53 wild-type or unknown status (regardless of MDM2 amplification status), and dose expansion in TP53 wild-type patients with or without MDM2-amplified disease.2
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.
Boehringer Ingelheim. Data on file.
ClinicalTrials.gov. NCT03449381. https://clinicaltrials.gov/ct2/show/NCT03449381 (Accessed: September 2018).
Rudolph D, et al. Presented at the Annual Meeting of the American Association for Cancer Research 2018. Abstract 4868 and poster.
Rinnenthal J, et al. Presented at the Annual Meeting of the American Association for Cancer Research 2018. Abstract 4865 and poster.
Zhao Y, et al. Acta Biochim Biophys Sin (Shanghai) 2014;46(3):180–9.
Montes de Octa Luna R, et al. Nature 1995;378(6553):203–6.
Ringhausen I, et al. Cancer Cell 2006;10(6):501–14.
Nag S, et al. J Biomed Res 2013;27(4):254–71.
Landré V, et al. Oncotarget 2014;5(18):7988–8013.
Shangary S, et al. 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.
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Last updated: May 2019
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