Targeting MDM2-p53 in cancer: The story of brigimadlin

Soft-tissue sarcomas (STS) are a group of rare and heterogeneous tumors arising in the soft tissues of the body such as muscle, nerves, blood vessels and fatty and fibrous tissues. There are at least 80 different histologic and molecular subtypes of STS, with different patterns of clinical behavior. DDLPS is an aggressive subtype of STS and one of the least responsive to chemotherapy. People living with DDLPS have had no new first-line treatment options in nearly five decades ¹. 

MDM2 and p53 in cancer

p53 is commonly referred to as the “Guardian of the Genome” due to its key role in protecting DNA integrity of cells. In normal cellular conditions, p53 is kept at low levels by the binding of its negative regulator MDM2 (murine double minute 2), which promotes p53 degradation. If a cell is exposed to stress, such as DNA damage, p53 jumps into action to control DNA repair or induce cell death (if damage cannot be repaired) ².

Cancer cells have developed strategies to inactivate p53’s tumor suppressor function. One mechanism is via mutations in the p53 gene – this represents approximately 50% of all cancers, making p53 the most frequently mutated gene in cancer ³. The other strategy is through increasing MDM2 levels. MDM2 amplifications (an increase in the copy number of the MDM2 gene) are most prevalent in sarcomas and occur in nearly all DDLPS cases ⁴. These amplifications lead to increased levels of the MDM2 protein, consequently, depleting p53. Therefore, blocking the MDM2–p53 interaction is considered a promising therapeutic strategy to restore wild-type (non-mutated) p53 function and induce death of cancer cells. 

Breaking through the walls of drug design and chemical development

Proteins play a key role in several biological processes. They catalyze reactions, transport molecules, but also control cell death as with p53. Many of these activities are regulated through protein–protein interactions (PPIs) - physical contacts between two or more protein molecules. This describes the interaction between MDM2 and p53. 

Targeting PPIs with small molecule inhibitors is conventionally considered highly challenging. The strong binding constant and the large binding interface between protein molecules can be hard to overcome with a small molecule ⁵. Thus, to tackle the MDM2-p53 interaction, we needed to design a PPI inhibitor that binds to the large p53-binding pocket of MDM2 and, in doing so, displaces the tightly binding p53. What makes targeting MDM2 particularly challenging is that when a drug binds to MDM2, a feedback loop causes the expression of MDM2 to skyrocket, quickly neutralizing the drug’s effectiveness. 

But these were not the only challenges that our scientists had to face. Literature suggested that inhibition of the MDM2-p53 interaction impaired the development of neutrophils and platelets that are essential cells in the blood, leading to a serious condition called thrombocytopenia ⁶. This is when the R&D team decided to design a potent compound with highly optimized pharmacokinetics that could be dosed intermittently, potentially opening the therapeutic window. This strategy would enable us to hit cancer cells hard, effectively driving them to cell death, but also allowing time for the hematopoietic system to recover.

Norbert Kraut, Global Head of Cancer Research at Boehringer Ingelheim, recalls “A few years after we started the project, I had the opportunity to present our research pipeline to an advisory board of clinical investigators. When I presented this program and our goal to deliver a super potent compound for infrequent dosing in the clinic, there was a lot of excitement in the room! This was our first protein-protein interaction target in oncology. We had a lot to learn. But we were quite bold, courageous and had a steep learning curve throughout the entire phase of drug discovery.”

Rigidification as key to success 

In medicinal chemistry and drug design, rigidification is the process of reducing the flexibility of a molecule. By using rigidification as a guiding design principle and after considerable effort to optimize the molecule, we were able to create a highly rigidified, potent and selective compound with excellent pharmacokinetic properties that met our dosing requirements. In 2016, the oral compound BI 907828 (now known as Brigimadlin), started pre-clinical development.

The rigid structure of Brigimadlin can be recognized by its large fused ring system: note below the high number of rings in close proximity.
 

Mastering Complexity: The art of producing Brigimadlin at scale

Brigimadlin did not spare our scientists in chemical development from challenges. The teams had only a matter of months to develop and optimize a new synthetic route to produce kilogram quantities of the highly complex structure of Brigimadlin. 

Annika Gille, Principal Scientist in Chemical Development at Boehringer Ingelheim, had just started her postdoc at our site in Biberach, Germany, when she was offered a position as Lab Head to run this ambitious project. “It was a great opportunity and learning experience. We had a combination of all possible challenges for process development in this project. But we took the time and dedicated the resources to fully figure out the chemistry. This was only possible through amazing teamwork and support from our management. We worked early on and closely across our internal groups, departments and R&D sites, which required seamless coordination and planning. For example, to achieve the tight timelines, while one team was optimizing the synthesis, other teams were already working in parallel to optimize the process to scale up for manufacturing, and search for better alternatives for the next manufacturing demands”.

Brigimadlin, our investigational MDM2-p53 antagonist, is the most advanced oncology asset from our cancer-cell directed pipeline research. It is currently being investigated in a Phase III clinical trial for the treatment of DDLPS (ClinicalTrials.gov Identifier: NCT05218499) and in a Phase IIa/IIb clinical trial for the treatment of advanced or metastatic MDM2-amplified TP53 wild-type biliary tract and pancreatic cancers (Clinicaltrials.gov identifier: NCT05512377). 

“This was from the beginning a very attractive precision medicine concept in oncology. We had several medicinal chemistry challenges - It has always been a challenge to tackle this PPI. But our perseverance, passion for science and commitment to patients gave us the courage to pursue this journey ahead. This is the first of multiple exciting assets in our oncology pipeline that will potentially deliver meaningful advances for people living with cancer.” adds Norbert Kraut.

Together we can change lives

Our purpose is to transform lives for generations. Our curiosity, creativity and passion for science lead us to take the paths scientifically less travelled and the courage to face challenging journeys as we relentlessly pursue the next generation of breakthrough therapies. This is only possible with the support of our exceptional people and global family of partners, who share the same passion for science and enjoy working together to deliver breakthroughs. 

Join us to grow, collaborate, innovate and transform lives for generations.

Explore our careers opportunities

Learn about our partnering interests in Oncology
 

References

1. Schöffski, P. Established and experimental systemic treatment options for advanced liposarcoma. Oncol. Res. Treat. (2022) doi:10.1159/000524939.
2. Zhao, Y., Yu, H. & Hu, W. The regulation of MDM2 oncogene and its impact on human cancers. Acta Biochim. Biophys. Sin. (Shanghai). 46, 180–189 (2014).
3. Chen, X. et al. Mutant p53 in cancer: from molecular mechanism to therapeutic modulation. Cell Death Dis. 13, 974 (2022).
4. Momand, J., Jung, D., Wilczynski, S. & Niland, J. The MDM2 gene amplification database . Nucleic Acids Res. 26, 3453–3459 (1998).
5. Lu, H. et al. Recent advances in the development of protein–protein interactions modulators: mechanisms and clinical trials. Signal Transduct. Target. Ther. 5, (2020).
6. Iancu-Rubin, C. et al. Activation of p53 by the MDM2 inhibitor RG7112 impairs thrombopoiesis. Exp. Hematol. 42, 137-145.e5 (2014).