The term “undruggable” has entered common industry vernacular over the past two decades to describe biologic targets that couldn’t be addressed via narrow conventional pharmacologies involving catalytic-site inhibitors and antibodies.
The “druggable genome” historically included intracellular catalytic proteins, (e.g., enzymes like kinases) and extracellular or transmembrane targets (e.g., ion channels, receptors, secreted proteins), representing only a small fraction of the human proteome – maybe 10 percent. But new therapeutic modalities have emerged that offer the potential to open the rest of the proteome to exploration, including targets like transcription factors, scaffolds in protein complexes, and signaling adaptor molecules.
Targeted protein degradation is one of the most compelling of these new modalities: this approach works by creating heterobifunctional chemistries which are able to simultaneously bind to proteins inside of cells and tag them for degradation by hijacking the cell’s normal protein disposal machinery, the ubiquitin-proteasome system. It’s an elegant, catalytic mechanism creating post-translational, chemically-induced knockdown of disease-causing proteins, and thus offers enormous potential to address previously intractable targets.
Today, Kymera Therapeutics, a new company in the space, is publicly launching out of stealth mode. Kymera aims to create a world-leading therapeutics platform in this emerging field, discovering and developing novel first-in-class medicines that offer unique degradation-induced pharmacology that we believe will result in clinically differentiated efficacy.
But before jumping into the Kymera story, it’s worth exploring the history of the field and what makes the modality so special – which forms the backdrop for what got Atlas Venture excited about this technology.
Brief History of Targeted Protein Degradation
Most proteins are degraded through the proteasome as part of normal turnover; in fact, the ubiquitin-proteasome system is the primary conduit for the majority of protein turnover and removal of misfolded proteins in eukaryotic cells. They get tagged with ubiquitin, a small protein recognized by the cell’s trash process, via enzymes called E3 ligases. Once tagged, these proteins are unfolded and channeled into the proteasome, a multi-subunit catalytic machine that is effectively the garbage disposal of the cell, cutting proteins into smaller peptide fragments. The rules of this process have been the subject of lots of exploration since the 1980s (like one of my favorites, Varshavsky’s N-end rule). By coincidence, several chapters of my graduate thesis in the 1990s described how the proteasome degrades antigenic proteins and helps process them for presentation to the immune system. Because of that connection, I’ve always loved the elegance of the proteasome system, and perhaps that’s why this modality has been of great interest to me for years.