How to knock down proteins driving disease processes in a cell
Many diseases are caused by the overproduction of certain proteins. The traditional approach to interfere with these proteins is based on small molecules or antibodies blocking these proteins or their corresponding target, e.g., receptors. Thanks to the recent progress of nucleic acid research, there are several new approaches today which intervene at different stages, from gene regulation to transcription to translation: CRISPR-Cas9 methods to target the DNA, zinc finger repressors targeting gene transcription, or RNA-molecules (antisense oligonucleotides, RNA interference, micro RNAs, etc.) to inactivate the mRNA or to suppress the translation. All approaches come with advantages and disadvantages. The main problem with DNA- and RNA-based medicine is delivery, followed by off-target-effects.
There are, however other new knockdown strategies as well, e.g., enhancing the protein clearance pathways to speed up the degradation of unwanted proteins, such as the autophagy-lysosome pathway and the ubiquitin-proteasome system (UPS).
Transcriptomics, data analysis, and AI/ML platforms as basis for partnership with BMS in targeted protein degradation
Since 2018, the latter technology of targeted protein degradation is also being used in a cooperation with Bristol Myers Squibb (BMS) to identify first-in-class drug candidates in oncology to treat solid tumors. For this collaboration, Evotec uses its PanOmics platform, EVOpanOmics, which combines enhanced throughput proteomics, high-throughput transcriptomics, and cell imaging with the integrated data analysis platform EVOpanHunter and Evotec’s AI/ML-based drug discovery and development platforms.
This research has led to the discovery of novel first-in-class molecular glue degraders. These small, drug-like compounds induce interactions between an E3 ubiquitin ligase and a molecular target, leading to ubiquitination and subsequent degradation of the recruited protein. The resulting therapeutic effect is long-lasting as the molecular glue degraders themselves are not degraded in the process and can initiate the degradation process through several iterations. BMS is a leader in this field based in particular on its unique library of cereblon E3 ligase modulators (CELMoD®) with specific protein-binding properties. Based on the needs of this project, Evotec focused on the development of dedicated and innovative software solutions that greatly helped to accelerate not only the project’s progress but also contributed to the overall progression of Evotec’s PanHunter platform.
The approach has generated a pipeline of novel first-in-class programs, two of which have transitioned successfully into lead optimization after completing respective validation processes on Evotec’s platforms. In this context, Evotec´s integrated data analysis platform panHunter and the Company’s AI and machine learning tools are used to quickly screen, share, and validate results – not only by Evotec, but also by BMS scientists. In May 2022, the partnership was expanded even further for an additional 8 years with the goal to once again broaden and deepen the strategic alliance.
Targeted protein degradation is not only useful in oncology – a number of other diseases, e.g. Alzheimer’s, bacterial and viral infections lead to the presence of unwanted proteins inside cells that may be marked for destruction by this powerful technology. Evotec therefore is welcoming partners interested in exploring this approach in collaborations.
To learn more about the BMS collaboration and the use of targeted protein degradation technology read the official press release.