Therapeutics Controlling Protein Turnover - Dr. Juliet Williams
Oct 21, 2023
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Dr. Juliet WIlliams of Kymera discusses the use of molecular linkers to connect proteins that need to be degraded with the machinery to tag them for destruction, targeting proteins for degradation as a therapeutic approach, exploring the potential of targeted protein degradation in treating various diseases, and the exciting technology and sponsorship opportunities for the podcast.
Targeted protein degradation offers the potential to target a wide range of disease-causing proteins, regardless of their mutation or role in signaling pathways.
The field of targeted protein degradation is expected to expand, with new E3 ligases being used as molecular glues and more therapeutic areas being explored.
Deep dives
Targeted Protein Degradation: Harnessing the Body's Natural System
Targeted protein degradation involves utilizing the natural protein recycling system in cells to selectively eliminate disease-causing proteins. Cells have proteins called E3 ligases that tag unwanted proteins with ubiquitin, which is then recognized by the cell's recycling system, the proteasome, for degradation. Heterobifunctional molecules and molecular glues are used to bring the E3 ligase in close proximity to the target protein, leading to ubiquitination and subsequent degradation. This approach allows for the degradation of a wide range of disease-causing proteins, regardless of their mutation, amplification, or role in signaling pathways. By degrading proteins with heterobifunctionals and molecular glues, targeted protein degradation offers the potential to target previously undrugged proteins or proteins that may have inadequate drug options available.
Specific Applications of Targeted Protein Degradation
Targeted protein degradation has shown promise in several disease areas. For example, the degradation of IRAC-4, a protein involved in immune response, has demonstrated effective anti-inflammatory effects in diseases like hydrogenitis superativir and atopic dermatitis. Other targets being explored include STAT3, a transcription factor implicated in cancer, and MDM2, a protein that regulates the tumor suppressor P53. The catalytic nature of degraders allows for highly potent molecules that can completely block disease pathways. This technology offers a new therapeutic approach for a wide range of diseases, including those with large patient populations and limited treatment options.
The Future of Targeted Protein Degradation
The field of targeted protein degradation is expected to expand in the future. More E3 ligases, in addition to cereblon and VHL, are likely to be used as heterobifunctionals and molecular glues, opening up new possibilities for protein targeting. This technology is not limited to specific diseases or tissues and can be applied in a disease-agnostic manner. The use of degraders in oral drugs and the ability to select E3 ligases specific to certain diseases or tissue sites further enhances the therapeutic potential. The field is actively exploring different targets and therapeutic areas, with a focus on high-need populations and areas where targeted protein degradation can transform standard care.
While DNA captures most of the fanfare, proteins are the catalytic and structural superstars of the cell. However, they can also become problematic. Cells have intricate mechanisms to remove damaged or mis-expressed proteins that could be deleterious to cellular function. This process is mediated by a process called ubiquitination, mediated by a special class of proteins called E3 ligases. Ubiquitin is the tag that's added that signals that a protein should be moved to the biochemical garbage can. Dr. Juliet WIlliams of Kymera describes how their company has used modeling and A.I. to design molecular linkers that connect a protein that needs to be degraded with the machinery to tag it for destruction. The goal of this line of therapeutics is to target a suite of proteins that need to be degraded for normal health and development. Their pipeline contains multiple clinical and pre-clinical trials, and the approach is an exciting complement to other drug discovery methods.
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