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 discovering and exploiting unique therapeutic modalities accessed by natural products. Our third research area focuses on using chemoproteomics-enabled covalent ligand discovery platforms to expand the scope of targeted protein degradation and to discover 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 platforms to tackle the undruggable proteome
One of the biggest challenges in curing human diseases is that most, 90 %, of the proteome is considered “undruggable”—most proteins are devoid of known functional binding pockets or “ligandable hotspots” that drugs can bind to modulate their functions for disease therapy. Developing new approaches to both discover binding pockets or “ligandable hotspots” and to pharmacologically target these sites with small-molecules will radically expand our scope of the druggable proteome and lead to new disease cures. Multiple technologies have arisen to tackle the undruggable proteome. One major strategy is a chemoproteomic platform termed activity-based protein profiling (ABPP) that uses reactivity-based chemical probes to map proteome-wide reactive, functional, and druggable hotspots directly in complex proteomes. When used in a competitive manner, covalent ligands can be competed against reactivity-based probe binding to druggable hotspots to pharmacologically target undruggable proteins. A major focus of our lab is to couple the target-based, biochemical, phenotypic screening of covalent ligand libraries with chemoproteomic platforms to rapidly discover new therapeutic small-molecule ligands, ligandable hotspots, and targets against undruggable proteins, pathways, and diseases.
Natural products isolated from microbes, plants, and other living organisms have been a tremendous source of therapeutics and comprise about 50 % of the drugs that are used for disease therapies. Many natural products are able to access unique therapeutic modalities that would usually be considered “undruggable.” Our lab has been using chemoproteomic platforms to discover novel therapeutic modalities targeted by natural products so that we can exploit these new modalities with more synthetically tractable covalent ligands.
Another groundbreaking technology enabling drug discovery efforts against undruggable targets is termed targeted protein degradation that exploits cellular protein degradation machinery to selectively eliminate target proteins. Targeted protein degradation involves the utilization of heterobifunctional molecules called “degraders” that consist of protein-targeting ligands linked to E3 ligase recruiters to bring E3 ligases in close proximity to specific proteins to ubiquitinate and proteasomally-degrade these targets. The promise of this strategy is that targeted protein degradation can be used to potentially target and degrade any protein target in the proteome, including the undruggable proteome. However, two major challenges exist in the application of this technology. First, undruggable targets by definition are likely not to possess ligands that bind to them. Second, while there are >600 E3 ligases, there are only a few E3 ligase recruiters that can be used for targeted protein degradation applications. Our lab is using chemoproteomic platforms to expand the scope of targeted protein degradation by: 1) discovering ligands against undruggable protein targets that can be used for degrader applications; and 2) discovering new E3 ligase recruiters. Beyond targeted protein degradation, we are also using chemoproteomic platforms to develop recruiters against other enzymes beyond E3 ligases that confer or remove protein post-translational modifications (PTMs) (e.g. deubiquitinases, phosphatases, deacetylases, etc) to manipulate protein PTMs and function in a targeted manner. Beyond heterobifunctional modalities, we are also focused on expanding on molecular glue scaffolds. Molecular glues are monovalent molecules that are capable of inducing the proximity of proteins that usually do not interact with each other to confer new protein functions. We are using chemoproteomic technologies to discover new molecular glue that target undruggable proteins for therapeutic applications.
- Boike L*, Cioffi AG*, Majewski FC, Co J, Henning NJ, Jones MD, Liu G, McKenna JM, Tallarico JA, Schirle M, Nomura DK. (2020) Discovery of a functional covalent ligand targeting an intrinsically disordered cysteine within MYC. In press at Cell Chemical Biology (*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 https://doi.org/10.1038/s41589-020-0557-2. PMID 3257277 (*co-corresponding author)
- Tong B*, Spradlin JN*, Novaes LFT, Zhang E, Hu X, Moeller M, Brittain SM, McGregor LM, McKenna JM, Tallarico JA, Schirle M, Maimone TJ#, Nomura DK#. (2020) A nimbolide-based kinase degrader preferentially degrades oncogenic BCR-ABL. ACS Chemical Biology doi: 10.1021/acschembio.0c00348. PMID 32568522 (*co-first authorship; # co-corresponding authorship)
- 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
- Berdan CA, Ho R, Lehtola HS, To M, Hu X, Huffman TR, Petri Y, Altobelli CR, Demeulenaere SG, Olzmann JA, Maimone TJ*, Nomura DK* (2019) Parthenolide covalently targets and inhibits focal adhesion kinase in breast cancer cells. Cell Chemical Biology 26, 1027-1035. PMID 31080076 (*co-corresponding authorship)
- Grossman E*, Ward CC*, Spradlin JN, Bateman LA, Huffman TR, Miyamoto DK, Kleinman JI, Nomura DK. (2017) Covalent ligand discovery against druggable hotspots targeted by anti-cancer natural products. Cell Chemical Biology 24, 1368-1376. PMID 28919038 (*co-first authorship)
- Bateman LA#, Nguyen TB#, Roberts AM#, Miyamoto DK, Ku W-M, Huffman TR, Petri Y, Heslin MJ, Contreras CM, Skibola CF, Olzmann JA*, Nomura DK*. (2017) Chemoproteomics-enabled covalent ligand screen reveals a cysteine hotspot in Reticulon 4 that impairs ER morphology and cancer pathogenicity. Chemical Communications 53, 7234-7237. PMID 28352901 (#co-first authors; *co-corresponding author)
- Roberts AM, Ward CC, Nomura DK. (2017) Activity-based protein profiling for mapping and pharmacologically interrogating proteome-wide ligandable hotspots. Current Opinion in Biotechnology 43, 25-33. PMID 27568596
Last Updated 2020-09-15