MFB: Developing Next-Generation Approaches to Targeted Protein Degradation

With the support of the Division of Chemistry (Molecular Foundations for Biotechnology Solicitation) and Division of Physics (Physics of Living Systems Program), Daniel K. Nomura and Thomas J. Maimone of University of California-Berkeley are developing new chemical biology approaches to degrade specific protein targets in the cell.

One of the biggest challenges facing drug discovery is that greater than 90% of the proteome is currently considered “undruggable” because most proteins do not possess known binding pockets that can be effectively targeted with small-molecule inhibitors for therapeutic benefit. Tackling the undruggable proteome requires the development of innovative technologies to nonetheless target such proteins with active sites that are shallow or otherwise do not lend themselves to small molecule binding.

This proposal is focused on combining a chemical biology platform for drug discovery with new therapeutic modalities that use small molecules to induce the proximity of two proteins that otherwise would not interact to induce the degradation of the targeted protein. Proof of principle of this approach is expected have broad long term scientific impacts on the field of targeted protein degradation.

Developing new therapeutic paradigms to benefit society requires investments in education at both the undergraduate and graduate levels, particularly in the rapidly growing field of chemical biology. This program seeks to expand on modern small molecule drug discovery elements in the UC-Berkeley classroom and to expose Bay Area community college transfer students to the excitement and opportunities in this area at the B.S. level and as careers.

Additionally, the Nomura and Maimone laboratories will synergize their respective STEM (science, technology, engineering and mathematics) outreach activities at the K-6 level as part of the Bay Area Scientists in Schools (BASIS) program.

In this proposal, the principal investigators will be using chemoproteomics-enabled covalent ligand discovery platforms to develop next-generation approaches to targeted protein degradation. Targeted protein degradation has arisen as a powerful therapeutic modality that uses either heterobifunctional or monovalent small-molecules, also known as Proteolysis Targeting Chimeras (PROTACs) or molecular glue degraders, respectively, to induce the proximity of an E3 ubiquitin ligase with a neo-substrate protein to ubiquitinate and proteasomally degrade the neo-substrate protein in cells.

However, several challenges exist with PROTACs and molecular glue degraders, including potential resistance mechanisms, linker optimization, or poor rational design principles. The investigators will develop novel and next-generation approaches to targeted protein degradation that have the potential to be transformative and overcome many of the current challenges in the field.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.