Protein Degradation: New Rules for Drug Discovery

Breakthroughs in technology have revolutionized how we think about new medicines and have brought life-saving treatments to millions of patients. Yet despite all we’ve learned about genomics and proteomics, we have only begun to scratch the surface when it comes to our knowledge of how to leverage or modify the human bodies’ complex cellular mechanisms.

Lately, a tremendous amount of interest and investment has focused on the field of targeted protein degradation, which has been viewed by many as the most promising new therapeutic modality since CRISPR gene editing. Targeted protein degraders are bifunctional small molecules with the potential to address previously “undruggable” and difficult-to-drug targets in the human proteome — the thousands of proteins responsible for sickness and health. The proteome is exceptionally fertile terrain for drug hunters, since conventional therapeutics modalities can access only about 10-20% of the proteins we make.

Protein degraders have two active ends: one that binds to the protein of interest and the other that binds to a protein called E3 ubiquitin ligase. They act like enzymes or catalysts, with the E3 ligases marking and sending proteins for disposal to the proteasome, the cell’s trash compactor.

The measure of a protein degrader is not the tightness of its binding to the protein but rather the speed by which it can bring all the right pieces together to recruit, tag and route the targeted proteins. This shift of MOA from binding to reaction kinetics, coupled with the ability to access novel biology through drugging novel classes of targets, are why the pharmaceutical industry and investors are so optimistic about this modality’s potential to hit previously unreachable targets. In fact, as a recent Chemical & Engineering News article notes,

If companies want to access the other 80% of the proteome, their medicinal chemists will need to forge a new set of rules for how to rationally build drugs that consistently degrade proteins.”

Going Deeper in Understanding Protein Degradation

The need to establish well-defined operating principles has been a central driver of Kymera’s research in this emerging field. When we started the company in early 2016, our idea was to build a team of experienced drug hunters to gain a deep understanding of the core functions and components of the entire protein degradation process. To deliver a powerful drug discovery engine, our efforts have focused on:

• Identifying the ligandable proteins in the unexplored proteome.
• Understanding the relationship between target proteins and E3 ligases to guide selection and further E3 exploration.
• Dissecting the key process steps — from cell permeability to target engagement to protein degradation — to drive specific structure activity relationships (SAR).
• Resolving critical issues with existing E3 ligands such as chemical and metabolic stability and/or ways to improve their existing biological or pharmacological profile.
• Moving beyond phenotype-based monitoring to better understand proteome-wide regulations and the specificity of the degradation process.
• Developing assays capable of decoupling degradation from earlier steps in the biochemical cascade, which will lead to a better understanding of the specific SARs of the degraders necessary for their optimization.

Components of a Rationally Designed Protein Degrader Platform

Although the human ubiquitin-proteasome machinery includes more than 600 E3 ligases, the ligands that have been identified to date bind to only a handful of them. Most of these were identified either through MOA studies of existing drugs or via drug discovery campaigns towards E3 ligase inhibition – less than ideal methods for the purpose of targeted protein degradation.

Kymera has engineered a drug discovery platform designed to move beyond empirical studies of purely phenotypic cellular reactions to a predictive, proactive approach based on understanding each step of this elegant cascade. We have developed a holistic strategy that also focuses on accessing novel E3 ligase biology and binders through our rationally designed Pegasus™ platform, which includes:

• Informatics-driven selection of targets, E3 ligases and disease pathways
• Integrated hit ID capabilities, including a state-of-the-art, DNA-encoded library screening platform
• Proprietary ternary complex predictive modeling capabilities that facilitate the best pairings of target proteins with E3 ligases and increase probabilities for success
• Proprietary degradation tools, including linkers and protein-binding ligands

By gaining proprietary insights into these mechanisms, we will be better able to rationally design and develop next-generation protein degrading therapeutics.

Leveraging the DNA Libraries and Expertise of GSK

To further expedite our efforts, we recently formed a partnership with GSK, a pharmaceutical industry pioneer that formed the first research unit dedicated to protein degradation in 2012. This collaboration gives Kymera access to GSK’s DNA-encoded libraries – the longest standing platform in the field – which can be used to scan trillions of compounds tagged with DNA bar codes that can then be sequenced to reveal the structure of any hits.

Through its extensive experience in targeted protein degradation, GSK has achieved a sophisticated, pragmatic understanding of this novel science, including its potential opportunities and challenges. Its institutional knowledge will serve both companies well as we work together on select protein degradation targets of mutual interest to discover novel drug candidates and collaborate on discovering novel E3 ligases ligands.

All-in for the Long Haul

Kymera is all-in on targeted protein degradation. We are working to categorically answer all of our questions, seek and develop new solutions, and identify a path forward for rationally designed drug discovery – to own this process from beginning to end. The opportunity is clear. This promising therapeutic modality has the potential to deliver truly breakthrough therapies for patients who have no other treatment options. It doesn’t get more exciting than this.