Small Molecule Drug Discovery 

Leveraging technologies to innovate for patients 

Pushing the boundaries with new technologies in small molecule drug discovery is enabling us to find candidates for targets that previously seemed undruggable with traditional methods. We are employing approaches like structure-based drug design in combination with AI-driven methods, which enhances our ability to navigate the vast chemical space effectively. This process involves identifying the right starting point and then providing guidance to our scientists on the direction to take. The ultimate goal of these efforts is to discover innovative drugs that can significantly improve the lives of patients. 

Research topics in Small Molecule Drug discovery  

Structure-based drug design 

 In March 2022, a new high-resolution microscope was put into service at the Institute of Molecular Pathology (IMP) in Vienna. IMP and Boehringer Ingelheim researchers are now sharing microscope time equally, enabling fast access for Boehringer Ingelheim scientists as well as high-end research at the IMP. At Boehringer Ingelheim, we apply cryo-EM to a variety of projects, most importantly for the determination of structures of multiprotein complexes, integral membrane proteins, new biological entities, and PROTAC-mediated ternary complexes of E3 ligases.  

Degrader modalities 

The promise of protein degraders is that they offer real hope for creating drugs against disease-causing proteins that have previously been considered undruggable. This approach is fundamental to Boehringer Ingelheim’s oncology research strategy. The goal for the small molecule drug discovery team in Vienna is to create first-in-class drugs for patients for whom there are currently very limited treatment options. Protein degraders, such as PROTACs, offer a potentially highly effective way to address so-called hard-to-drug targets, such as KRAS. PROTACs are two-faced small molecules, welded together by a linker. One end selectively binds to the target disease-causing protein and a second end recruits a cellular protein from the E3 ubiquitin ligase family. Once connected, the ligase tags the cancer-causing protein for destruction. The tagged protein is then degraded by the cell’s waste disposal system rendering it inactive and initiating cancer cell selective cell-death. 

Covalent drugs 

Covalent drugs, where the molecule forms an irreversible bond to its target, may provide many pharmacological advantages over reversible drugs, and are of continued research interest at Boehringer Ingelheim. We discovered the drug candidate that selectively inhibits human epidermal growth factor receptor 2 (HER2) in non-small-cell lung cancer (NSCLC). Oncogenic mutations in HER2 occur in approximately 2–3% of patients with NSCLC. Many of the current inhibitors are limited by their activity against the wild-type epidermal growth factor receptor (EGFR), causing dose-limiting, off-target toxicities. The new covalent inhibitor binds selectively and covalently to the tyrosine kinase domain of both wild-type and mutated HER2 receptors, while sparing wild-type EGFR signaling, thereby avoiding toxicity. This inhibitor is being developed as an oral treatment for patients with specific mutations in the HER2 gene and is currently in clinical trials Phase III. 

Artificial intelligence and quantum computing 

Following the paradigm “predict before synthesis” we aim to predict a multitude of molecular properties relevant for medicinal chemistry for virtual molecules in silico before investing synthetic resources. Large scale machine learning models and artificial intelligence allow to explore the relevant chemical space more efficiently and prioritize where experimental efforts are focused. Thereby, we build on large amounts of internal data that have been gathered over decades in the company and serve as the basis for training of highly predictive models. In collaboration with universities in Vienna we explore the latest technologies in machine learnings and molecular dynamics simulations. In a joint effort with Google we explore the future potential of quantum computing in drug discovery.  Along these lines “predict before synthesis” also helps us to contribute to Boehringer Ingelheim’s sustainability goals. 

Photochemistry 

Photo redox chemistry, a field that uses light to catalyze reactions, has become a cornerstone in modern organic synthesis. The progress in this field, however, has often been hampered by non-standardized conditions and a lack of precise control over crucial parameters such as light intensity and temperature. To address these challenges our chemists designed a 3D-printed photoreactor, to improve the reproducibility of photochemical reactions, as well a temperature-controlled multi-well reactors technology, which allows for precise dosing of photo redox catalysts. The innovations in organic chemistry further enhance the efficiency and scope of these reactions. Boehringer chemists validated these technologies across various reaction classes. The successful reproduction and transfer of results to larger-scale platforms have demonstrated the potential of these advancements in high-throughput experimentation.