Targeted protein degradation (TPD) has arisen as a powerful drug discovery platform for tackling the undruggable proteome by targeting specific proteins for proteasomal degradation through the formation of ternary complexes facilitated by either small-molecule molecular glues or heterobifunctional degraders that bring together an E3 ubiquitin ligase with a neo-substrate protein. While this approach has exploded in popularity in cancer drug discovery, a major challenge includes the dearth of E3 ligase recruiters despite the abundance of >600 E3 ligases, and the very few examples of molecular glues and recruitment of neo- substrates for degradation. Another challenge of TPD is that it cannot be applied to protein substrates which are actively ubiquitinated and degraded like many tumor suppressors within cancer cells. To address these two challenges, I propose to utilize chemoproteomics-enabled covalent ligand discovery platforms to discover new E3 ligase recruiters for TPD applications and develop a new cancer drug discovery paradigm for targeted protein stabilization (TPS) for deubiquitinating and stabilizing tumor suppressors, through the discovery and application of deubiquitinase recruiters. Chemoproteomic platforms, such as activity-based protein profiling (ABPP), have arisen as powerful platforms to mapping and pharmacologically targeting proteome-wide ligandable sites. ABPP uses reactivity-based chemical probes to profile proteome-wide reactive, ligandable, and functional sites directly in complex proteomes. Here, I will use ABPP to discover an arsenal of covalent ligands against E3 ligases and deubiquitinases that can be applied for TPD and TPS. During the F99 graduate thesis phase of my fellowship, I will expand the scope of TPD by discovering new E3 ligase recruiters that can be used to proteasomally degrade cancer therapy targets. During this time, I will also attend national and international conferences, hone my skills in mentoring, take courses in responsible research conduct, hone my skills in paper and grant writing, and interview for postdoctoral positions towards expanding my knowledge, networking, and finding an optimal postdoctoral position. My graduate research environment is stellar at UC Berkeley and in the Nomura Research Group, where I have access to world-class professors and have interactions with top-notch graduate students and postdoctoral fellows, as well as cutting edge technologies and resources. During my K00 phase, I will advance the TPS platform to develop a new drug discovery paradigm for stabilizing the expression of tumor suppressors to develop a new type of cancer therapy. During this time, I will also continue to attend national and international conferences, hone my skills in mentoring, paper and grant writing, and public speaking, apply for the K99/R00 transition award, and apply for tenure-track professor positions at top-tier research institutions.
I propose to utilize chemoproteomics-enabled covalent ligand discovery platforms to discover new E3 ligase recruiters for targeted protein degradation applications and develop a new cancer drug discovery paradigm for targeted protein stabilization (TPS) for deubiquitinating and stabilizing tumor suppressors, through the discovery and application of deubiquitinase recruiters.
