Daniel K. Nomura
Professor of Biochemistry, Biophysics and Structural Biology*
*and of Chemistry and of Nutritional Sciences & Toxicology
The Nomura Research Group is focused on reimagining druggability using chemoproteomic platforms to develop transformative medicines. One of the greatest challenges that we face in discovering new disease therapies is that most proteins are considered “undruggable,” in that most proteins do not possess known binding pockets or “ligandable hotspots” that small-molecules can bind to modulate protein function. Our research group addresses this challenge by advancing and applying chemoproteomic platforms to discover and pharmacologically target unique and novel ligandable hotspots for disease therapy. We currently have three major research directions. Our first major focus is on developing and applying chemoproteomics-enabled covalent ligand discovery approaches to rapidly discover small-molecule therapeutic leads that target unique and novel ligandable hotspots for undruggable protein targets and pathways. Our second research area focuses on using chemoproteomic platforms to expand the scope of targeted protein degradation technologies. Our third research area focuses on using chemoproteomics-enabled covalent ligand discovery platforms to develop new induced proximity-based therapeutic modalities. Collectively, our lab is focused on developing next-generation transformative medicines through pioneering innovative chemical technologies to overcome challenges in drug discovery.
Chemoproteomics-Enabled Covalent Ligand Discovery against the Undruggable Proteome
Our first research area is focused on using chemoproteomics-enabled covalent ligand discovery platforms to rapidly uncover covalently acting fully synthetic or natural product-based therapeutic leads that target unique and novel ligandable hotspots against undruggable disease therapy targets and pathways. Using chemoproteomic approaches, we have identified >100,000 ligandable hotspots across >16,000 human protein targets and have identified ligandable sites against >90 % of known genetically linked drivers of human cancer. Our approach to tackle the undruggable proteome has been to perform target-based or phenotypic screening of our ever-expanding covalent ligand libraries to identify hit compounds and to use chemoproteomic platforms to rapidly assess target engagement, proteome-wide selectivity, target identification, and mechanism. We have already had significant success in discovering unique ligandable hotspots and developing functional covalent ligands against several high-value undruggable disease therapy targets.
Expanding the Scope of Targeted Protein Degradation using Chemoproteomic Platforms
Our second research area has focused on using chemoproteomics-enabled covalent ligand discovery platforms to expand the scope of targeted protein degradation (TPD) approaches. TPD is an innovative therapeutic modality to tackle the undruggable proteome by degrading specific disease-causing proteins. TPD utilizes small-molecules that can induce the proximity of a target protein with a component of the cellular protein degradation machinery to induce the degradation of specific disease-causing proteins. A major TPD approach utilizes Proteolysis-Targeting Chimeras (PROTACs)—heterobifunctional compounds that link a protein-targeting ligand to an E3 ubiquitin ligase recruiter—to recruit an E3 ligase to a specific target to ubiquitinate and degrade the target through the proteasome. While PROTACs are a very promising therapeutic strategy for destroying undruggable disease targets, there are currently also bottlenecks in achieving the full potential of PROTACs. First, ligand discovery against the undruggable protein targets remains challenging. Second, while there are >600 E3 ligases in the human genome, there are only a small number of E3 ligase recruiters that can be used for PROTAC applications. Our lab has been using chemoproteomic approaches to overcome both of these challenges. Chemoproteomics-enabled covalent ligand discovery platforms can be used to discover ligands and ligandable hotspots against undruggable proteins that can subsequently be used to develop PROTACs to degrade undruggable targets. Chemoproteomic approaches can also be used to discover new E3 ligase recruiters. Beyond PROTACs that recruit E3 ligases for TPD, we are developing next-generation heterobifunctional strategies that recruit other components of the cellular degradation machinery to expand the scope of TPD. Another innovative approach to TPD is molecular glues, monovalent small-molecules that induce the proximity of a target protein with E3 ligases to ubiquitinate and degrade target proteins of interest. Thus far, there have only been a small number of molecular glue degraders that have been mostly fortuitously discovered (e.g. thalidomide and the Immunomodulatory imide drugs (IMiDs)) and there have not been systematic approaches to discover new molecular glues and their targets or to rationally design molecular glue degraders. We are developing both discovery platforms and rational design principles to discover novel molecular glue degraders.
Discovering New Induced Proximity-Based Therapeutic Modalities
Our third research area has focused on using chemoproteomic platforms to enable the development of next-generation induced proximity paradigms beyond targeted protein degradation. Recruitment of E3 ligases is just the tip of the iceberg of other types of proteins and enzymes that can be recruited to specific target proteins to modulate their function for therapeutic applications. These new induced proximity-based therapeutic modalities exploit small-molecules to induce the proximity of proteins that usually do not interact to confer neomorphic protein functions for therapeutic benefit. We are combining chemoproteomic platforms with heterobifunctional and molecular glue based approaches to enable these new therapeutic paradigms.
Henning NJ, Boike L, Spradlin JN, Ward CC, Belcher B, Brittain SM, Hesse M, Dovala D, McGregor LM, McKenna JM, Tallarico JA, Schirle M, Nomura DK (2021) Deubiquitinase-targeting chimeras for targeted protein stabilization. BioRxiv, 44195
Spradlin JN, Zhang E, Nomura DK (2021) Reimagining Druggability using Chemoproteomic Platforms. Accounts of Chemical Research. https://doi.org/10.1021/acs.accounts.1c00065.
Luo M*, Spradlin JN*, Boike L, Tong B, Brittain SM, McKenna JM, Tallarico JA, Schirle M, Maimone TJ#, Nomura DK#. (2021) Chemoproteomics-enabled ligand discovery of covalent RNF114-based degraders that mimic natural product function. Cell Chemical Biology doi.org/10.1016/j.chembiol.2021.01.005. (*co-first authorship, # co-corresponding authorship)
Boike L*, Cioffi AG*, Majewski FC, Co J, Henning NJ, Jones MD, Liu G, McKenna JM, Tallarico JA, Schirle M, Nomura DK. (2021) Discovery of a functional covalent ligand targeting an intrinsically disordered cysteine within MYC. Cell Chemical Biology 28, 4-13. PMID 32966806 (*co-first authorship)
Isobe Y, Okumura M, White R, McGregor LM, Brittain SM, Jones MD, Liang X, White R, Forrester W, McKenna JM, Tallarico JA, Schirle M, Maimone TJ*, Nomura DK* (2020) Manumycin polyketides act as molecular glues between UBR7 and P53. Nature Chemical Biology 16, 1189-1198. PMID 3257277 (*co-corresponding author)
Chung CY-S*, Shin HR*, Berdan CA, Ford B, Ward CC, Olzmann JA, Zoncu R#, Nomura DK# (2019) Covalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibition. Nature Chemical Biology 15, 776-785. PMID 31285595 (*co-first authorship; #co-corresponding authorship)
Spradlin JN, Hu X, Ward CC, Brittain SM, Jones MD, Ou L, To M, Proudfoot A, Ornelas E, Woldegiorgis M, Olzmann JA, Bussiere DE, Thomas JR, Tallarico JA, McKenna JM, Schirle M, Maimone TJ*, Nomura DK* (2019) Harnessing the anti-cancer natural product nimbolide for targeted protein degradation. Nature Chemical Biology 15, 747-755. PMID 31209351 (*co-corresponding authors)
Ward CC, Kleinman JI, Chung CYS, Kim K, Petri Y, Lee PS, Thomas JR, Tallarico JA, McKenna JM, Schirle M, Nomura DK (2019) Covalent ligand screening uncovers a RNF4 E3 ligase recruiter for targeted protein degradation applications. ACS Chemical Biology 14, 2430-2440. PMID 31059647
Last Updated 2021-08-05