Current treatment approaches center on using small molecules to inhibit or modulate dysregulated proteins. Of the 21,000 proteins coded by the human proteome, 85 percent cannot be addressed by small molecule inhibition or modulation. This means there are millions of people living with diseases for which there are limited or no known treatment options.
Kymera’s therapeutics are designed to leverage and redirect the ubiquitin proteosome system (UPS), central to the regulation of cellular processes and the molecular biology of protein degradation. Using a small molecule-based knockdown strategy, we rationally design and develop heterobifunctional molecules or chimeras. These molecules recruit disease-causing proteins to E3 ubiquitin ligases, resulting in their ubiquitination and subsequent degradation.
Aaron Ciechanover, Avram Hershko, Irwin Rose and colleagues first discovered the cyclical cellular process of protein degradation in the 1980s – a groundbreaking discovery with enormous impact on biology and medicine that garnered them the Nobel Prize for chemistry in 2004. Most scientists at the time were interested in explaining how cells produce proteins but this team was driven to understand how proteins were broken down. They discovered that protein degradation is a controlled process. Proteins are marked for degradation once they bind to a molecule we now call ubiquitin, nature’s tag for proteasomal recognition and degradation, signaling to the proteasome to degrade the protein.
This discovery provided important insights into other ubiquitin-mediated protein degradation processes like cell division, DNA repair and more. It helped scientists understand the role of dysregulated protein degradation in certain diseases. And it also provided an important the initial input towards a new strategy or means to chemically redirect this cellular process to treat disease.