Overview
The Nomura Research Group is focused on reimagining druggability using chemical biology platforms to develop transformative medicines.
How we do it
One of the biggest challenges facing drug discovery is that >90 % of the proteome is currently considered “undruggable” because most proteins do not possess known binding pockets or “ligandable hotspots” that can be pharmacologically and functionally targeted for therapeutic benefit. Tackling the undruggable proteome requires the development of innovative technologies for ligand discovery AND the discovery of novel therapeutic modalities to functionally manipulate the undruggable proteome for therapeutic benefit. The Nomura Research Group is focused on reimagining druggability by advancing and applying chemoproteomic platforms to tackle the undruggable proteome, towards developing next-generation therapies and therapeutic modalities for human diseases. Our research is focused on three major themes to tackle the undruggable proteome—ligand discovery, expanding the scope of targeted protein degradation platforms, and developing new therapeutic modalities—for developing next-generation disease therapies.
Chemoproteomics-Enabled Covalent Ligand Discovery Against the Undruggable Proteome
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.
Targeted Protein Localization by Covalent 14-3-3 Recruitment
Shao Q, Duong TN, Park I, Orr LM, Nomura DK
JACS, 2024, https://doi.org/10.1021/jacs.3c12389. PMID 39196545
Covalent degrader of the oncogenic transcription factor b-catenin
Gowans FA*, Forte N*, Hatcher J, Huang OW, Wang Y, Altamirano Poblano BE, Wertz IE, Nomura DK
JACS, 2024, 146, 16856–16865. PMID 38848252 (*co-first authorship)
Rational Chemical Design of Molecular Glue Degraders
Toriki ES*, Papatzimas JW*, Nishikawa K, Dovala D, Frank AO, Hesse MJ, Dankova D, Song J-G, Bruce-Smythe M, Struble H, Garcia FJ, Brittain SM, Kile AC, McGregor LM, McKenna JM, Tallarico JA, Schirle M, Nomura DK
ACS Central Science, 2023, 9, 915-926. (* co-first authorship)
(Novartis-Berkeley Translational Chemical Biology Institute paper)
Chemoproteomics-Enabled Discovery of a Covalent Molecular Glue Degrader Targeting NF-kB
King EA, Cho Y, Hsu, NS, Dovala D, McKenna JM, Tallarico JA, Schirle M, Nomura DK
Cell Chemical Biology, 2023, 30, 394-402. PMID 36898369
(Novartis-Berkeley Translational Chemical Biology Institute paper)
Advances in covalent drug discovery
Boike L*, Henning NJ*, Nomura DK
Nature Reviews Drug Discovery, 2022, 21, 881-898. PMID 36008483 (*co-first authors)
Reimagining Druggability using Chemoproteomic Platforms
Spradlin JN, Zhang E, Nomura DK
Accounts of Chemical Research, 2021, 54, 1801-1813. PMID 33733731
Chemoproteomics-enabled ligand discovery of covalent RNF114-based degraders that mimic natural product function
Luo M*, Spradlin JN*, Boike L, Tong B, Brittain SM, McKenna JM, Tallarico JA, Schirle M, Maimone TJ#, Nomura DK#.
Cell Chemical Biology, 2021, 28, 559-566. PMID 33513350 (*co-first authorship, # co-corresponding authorship)
(Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper)
Discovery of a functional covalent ligand targeting an intrinsically disordered cysteine within MYC
Boike L*, Cioffi AG*, Majewski FC, Co J, Henning NJ, Jones MD, Liu G, McKenna JM, Tallarico JA, Schirle M, Nomura DK.
Cell Chemical Biology, 2021, 28, 4-13. PMID 32966806 (*co-first authorship)
(Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper)
Manumycin polyketides act as molecular glues between UBR7 and P53
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*
Nature Chemical Biology, 2020, 16, 1189-1198. PMID 32572277 (*co-corresponding author) (Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper)
Covalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibition
Chung CY-S*, Shin HR*, Berdan CA, Ford B, Ward CC, Olzmann JA, Zoncu R#, Nomura DK#
Nature Chemical Biology, 2019, 15, 776-785. PMID 31285595 (*co-first authorship; #co-corresponding authorship) (Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper)
Harnessing the anti-cancer natural product nimbolide for targeted protein degradation
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*
Nature Chemical Biology, 2019, 15, 747-755. PMID 31209351 (*co-corresponding authors) (Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper)
Covalent ligand screening uncovers a RNF4 E3 ligase recruiter for targeted protein degradation applications
Ward CC, Kleinman JI, Brittain SM, Lee PS, Chung CYS, Kim K, Petri Y, Thomas JR, Tallarico JA, McKenna JM, Schirle M, Nomura DK
ACS Chemical Biology, 2019, 14, 2430-2440. PMID 31059647 (Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper)
Parthenolide covalently targets and inhibits focal adhesion kinase in breast cancer cells
Berdan CA, Ho R, Lehtola HS, To M, Hu X, Huffman TR, Petri Y, Altobelli CR, Demeulenaere SG, Olzmann JA, Maimone TJ*, Nomura DK*
Cell Chemical Biology, 2019, 26, 1027-1035. PMID 31080076 (*co-corresponding authorship) (Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper)
Target identification of bioactive covalently-acting natural products
Nomura DK* and Maimone TJ*
Current Topics in Microbiology and Immunology, 2018, 420, 351-374. PMID 30105423 (*co-corresponding authorship)
Covalent ligand discovery against druggable hotspots targeted by anti-cancer natural products
Grossman E*, Ward CC*, Spradlin JN, Bateman LA, Huffman TR, Miyamoto DK, Kleinman JI, Nomura DK
Cell Chemical Biology, 2017, 24, 1368-1376.e4. PMID 28919038 (*co-first authorship)
NHS-esters as versatile reactivity-based probes for mapping proteome-wide ligandable hotspots
Ward CC, Kleinman J, Nomura DK
ACS Chemical Biology, 2017, 12, 1478-1483. PMID 28445029
Chemoproteomics-enabled covalent ligand screen reveals a cysteine hotspot in Reticulon 4 that impairs ER morphology and cancer pathogenicity
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*
Chemical Communications, 2017, 53, 7234-7237. PMID 28352901 (#co-first authors; *co-corresponding author)
Expanding the Scope of Targeted Protein Degradation using Chemoproteomic Platforms
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 using chemoproteomic approaches coupled with targeted cellular screens of our covalent ligand libraries to discover new molecular glue degraders and to rapidly deconvolute their ternary complex components.
Covalent degrader of the oncogenic transcription factor b-catenin
Gowans FA*, Forte N*, Hatcher J, Huang OW, Wang Y, Altamirano Poblano BE, Wertz IE, Nomura DK
JACS, 2024, 146, 16856–16865. PMID 38848252 (*co-first authorship)
DCAF16-based covalent handle for the rational design of monovalent degraders
Lim M*, Do Cong T*, Orr LM, Toriki ES, Kile AC, Lee E, Nomura DK
ACS Central Science, 2024, 10, 1318-1331. PMID 39071058 (*co-first authorship)
(Novartis-Berkeley Translational Chemical Biology Institute paper)
Exploiting the Cullin E3 ligase adaptor protein SKP1 for targeted protein degradation
Hong SH*, Divakaran A*, Osa A, Huang OW, Wertz IE, Nomura DK
ACS Chemical Biology, 2024, 19, 442-450. PMID 37904950. (*co-first authors)
Targeted protein degradation through recruitment of the CUL4 complex adaptor protein DDB1
Meyers M, Cismoski S, Panidapu A, Chie-Leon B, Nomura DK
ACS Chemical Biology, 2024, 19, 58-68. PMID 38192078
(Novartis-Berkeley Translational Chemical Biology Institute paper)
Rational Chemical Design of Molecular Glue Degraders
Toriki ES*, Papatzimas JW*, Nishikawa K, Dovala D, Frank AO, Hesse MJ, Dankova D, Song J-G, Bruce-Smythe M, Struble H, Garcia FJ, Brittain SM, Kile AC, McGregor LM, McKenna JM, Tallarico JA, Schirle M, Nomura DK
ACS Central Science, 2023, 9, 915-926. (* co-first authorship)
(Novartis-Berkeley Translational Chemical Biology Institute paper)
Chemoproteomics-Enabled Discovery of a Covalent Molecular Glue Degrader Targeting NF-kB
King EA, Cho Y, Hsu, NS, Dovala D, McKenna JM, Tallarico JA, Schirle M, Nomura DK
Cell Chemical Biology, 2023, 30, 394-402. PMID 36898369
(Novartis-Berkeley Translational Chemical Biology Institute paper)
Targeted Protein Degradation through E2 Recruitment
Forte N, Dovala D, Hesse MJ, McKenna JM, Tallarico JA, Schirle M, Nomura DK
ACS Chemical Biology, 2023, https://doi.org/10.1021/acschembio.3c00040. PMID 36940189
(Novartis-Berkeley Translational Chemical Biology Institute paper)
Ligandability of E3 Ligases for Targeted Protein Degradation Applications
Belcher B, Ward CC, Nomura DK
Biochemistry, 2023, 62, 588-600. PMID 34473924
Discovery of a covalent FEM1B recruiter for targeted protein degradation applications
Henning NJ*, Manford AG*, Spradlin JN, Brittain SM, Zhang E, McKenna JM, Tallarico JA, Schirle M, Rape M#, Nomura DK#
Discovery of a covalent FEM1B recruiter for targeted protein degradation applications.
JACS, 2022, 144, 701-708. PMID 34994556 (*co-first authorship; #co-corresponding authorship)
(Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper)
Reimagining Druggability using Chemoproteomic Platforms
Spradlin JN, Zhang E, Nomura DK
Accounts of Chemical Research, 2021, 54, 1801-1813. PMID 33733731
Chemoproteomics-enabled ligand discovery of covalent RNF114-based degraders that mimic natural product function
Luo M*, Spradlin JN*, Boike L, Tong B, Brittain SM, McKenna JM, Tallarico JA, Schirle M, Maimone TJ#, Nomura DK#.
Cell Chemical Biology, 2021, 28, 559-566. PMID 33513350 (*co-first authorship, # co-corresponding authorship)
(Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper)
Discovery of a functional covalent ligand targeting an intrinsically disordered cysteine within MYC
Boike L*, Cioffi AG*, Majewski FC, Co J, Henning NJ, Jones MD, Liu G, McKenna JM, Tallarico JA, Schirle M, Nomura DK.
Cell Chemical Biology, 2021, 28, 4-13. PMID 32966806 (*co-first authorship)
(Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper)
Bardoxolone Conjugation Enables Targeted Protein Degradation of BRD4
Tong B*, Luo M*, Xie Y, Spradlin JN, Tallarico JA, McKenna JM, Schirle M, Maimone TJ#, Nomura DK#
Scientific Reports, 2020, 10, 15543. PMID 32968148 (*co-first authorship; # co-corresponding authorship) (Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper)
Manumycin polyketides act as molecular glues between UBR7 and P53
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*
Nature Chemical Biology, 2020, 16, 1189-1198. PMID 32572277 (*co-corresponding author) (Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper)
A nimbolide-based kinase degrader preferentially degrades oncogenic BCR-ABL
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#
ACS Chemical Biology, 2020, 15, 1788-1794. PMID 32568522 (*co-first authorship; # co-corresponding authorship) (Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper)
Covalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibition
Chung CY-S*, Shin HR*, Berdan CA, Ford B, Ward CC, Olzmann JA, Zoncu R#, Nomura DK#
Nature Chemical Biology, 2019, 15, 776-785. PMID 31285595 (*co-first authorship; #co-corresponding authorship) (Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper)
Harnessing the anti-cancer natural product nimbolide for targeted protein degradation
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*
Nature Chemical Biology, 2019, 15, 747-755. PMID 31209351 (*co-corresponding authors) (Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper)
Covalent ligand screening uncovers a RNF4 E3 ligase recruiter for targeted protein degradation applications
Ward CC, Kleinman JI, Brittain SM, Lee PS, Chung CYS, Kim K, Petri Y, Thomas JR, Tallarico JA, McKenna JM, Schirle M, Nomura DK
ACS Chemical Biology, 2019, 14, 2430-2440. PMID 31059647 (Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper)
Discovering New Induced Proximity-Based Therapeutic Modalities
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.
Targeted Protein Localization by Covalent 14-3-3 Recruitment
Shao Q, Duong TN, Park I, Orr LM, Nomura DK
JACS, 2024, https://doi.org/10.1021/jacs.3c12389. PMID 39196545
Covalent degrader of the oncogenic transcription factor b-catenin
Gowans FA*, Forte N*, Hatcher J, Huang OW, Wang Y, Altamirano Poblano BE, Wertz IE, Nomura DK
JACS, 2024, 146, 16856–16865. PMID 38848252 (*co-first authorship)
Rational Chemical Design of Molecular Glue Degraders
Toriki ES*, Papatzimas JW*, Nishikawa K, Dovala D, Frank AO, Hesse MJ, Dankova D, Song J-G, Bruce-Smythe M, Struble H, Garcia FJ, Brittain SM, Kile AC, McGregor LM, McKenna JM, Tallarico JA, Schirle M, Nomura DK
ACS Central Science, 2023, 9, 915-926. (* co-first authorship)
(Novartis-Berkeley Translational Chemical Biology Institute paper)
Chemoproteomics-Enabled Discovery of a Covalent Molecular Glue Degrader Targeting NF-kB
King EA, Cho Y, Hsu, NS, Dovala D, McKenna JM, Tallarico JA, Schirle M, Nomura DK
Cell Chemical Biology, 2023, 30, 394-402. PMID 36898369
(Novartis-Berkeley Translational Chemical Biology Institute paper)
Deubiquitinase-Targeting Chimeras for Targeted Protein Stabilization
Henning NJ*, Boike L*, Spradlin JN, Ward CC, Liu G, Zhang E, Belcher BP, Brittain SM, Hesse M, Dovala D, McGregor LM, Veldez Misiolek R, Plasschaert LW, Rowlands DJ, Wang F, Frank AO, Fuller D, Estes AR, Randal KL, Panidapu A, McKenna JM, Tallarico JA, Schirle M, Nomura DK
Deubiquitinase-targeting chimeras for targeted protein stabilization.
Nature Chemical Biology, 2022, 18, 412-421. PMID 35210618 (* co-first authorship)
(Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper)
Reimagining Druggability using Chemoproteomic Platforms
Spradlin JN, Zhang E, Nomura DK
Accounts of Chemical Research, 2021, 54, 1801-1813. PMID 33733731
Discovery of a functional covalent ligand targeting an intrinsically disordered cysteine within MYC
Boike L*, Cioffi AG*, Majewski FC, Co J, Henning NJ, Jones MD, Liu G, McKenna JM, Tallarico JA, Schirle M, Nomura DK.
Cell Chemical Biology, 2021, 28, 4-13. PMID 32966806 (*co-first authorship)
(Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper)
Manumycin polyketides act as molecular glues between UBR7 and P53
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*
Nature Chemical Biology, 2020, 16, 1189-1198. PMID 32572277 (*co-corresponding author) (Novartis-Berkeley Center for Proteomics and Chemistry Technologies paper)