2 June 2025
The tumor suppressor protein p53, also known as TP53, is a crucial transcription factor that plays a pivotal role in regulating various cellular processes such as cell cycle arrest, DNA repair, and apoptosis. One of the central molecular control mechanisms of p53 activity and stability is its inhibition through the negative regulator MDM2. It acts as an E3 ligase and leads to the rapid proteasomal degradation of p53. Genetic disturbance of the fine-balanced protein-protein interaction between MDM2 and p53 has been found causal in the initiation and progression of certain subsets of cancers. These cancers are characterized by MDM2 overexpression, which leads to increased inhibition of wild-type p53 protein.
For these MDM2 elevated tumors, recent advancements in developing small molecule inhibitors of the MDM2-p53 interaction may offer a novel therapeutic strategy, especially for patients with TP53 wild-type tumors. However, there may be other instances where MDM2 upregulation may play a role.
To further investigate the roles of MDM2 and p53 in vitro and in vivo, we are providing the highly potent and selective MDM2-p53 protein-protein interaction antagonist BI-0282 via opnMe. BI-0282 demonstrated good potency (IC50 = 5 nM) for the inhibition of the MDM2-p53 protein-protein interaction in an AlphaScreen assay and displayed activity in rodent models. Additionally, we are offering the structurally similar but inactive analogue BI-0283 as a negative control. Interested researchers will receive these molecules for free and will have complete ownership of their results. We encourage researchers to publish their findings as part of our commitment to open science.
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About BI-0282:
BI-0282 is a small molecule antagonist that disrupts the interaction between the tumor suppressor p53 and its negative regulator MDM2 with single-digit nanomolar potency. It binds to the p53 binding pocket located at the N-terminus of the MDM2 protein, thereby preventing the binding of p53 to MDM2. This molecule demonstrates good permeability and cellular potency, making it suitable for oral dosing in in vivo studies. Notably, BI-0282 does not inhibit the E3 ubiquitin ligase activity of the MDM2 protein.
About opnMe:
opnMe.com, the open innovation portal of Boehringer Ingelheim, fosters science and collaboration initiatives in areas of high unmet medical need. As part of our first pillar, the “Molecules to Order”, we share well-characterized tool compounds free of charge with no IP strings attached. With our “opn2EXPERTS” program, we enlist scientific advice on key biologic issues to fuel further drug discovery and deliver novel solutions that benefit unmet patient needs. Learn more about our recent opn2EXPERTS call to improve the control of impulsivity and compulsivity. Our current opn2TALENTS PostDoc grant for more sustainable parasiticides, provides an opportunity for high-caliber talents to pitch their scientific ideas with the goal to conduct their research at our discovery research site in Biberach, Germany.