About

Dan Nomura is a Professor of Chemical Biology and Molecular Therapeutics in the Department of Chemistry and the Department of Molecular and Cell Biology at the University of California, Berkeley. He is also an Investigator at the Innovative Genomics Institute and the Co-Director of the UC Berkeley Molecular Therapeutics Initiative. His research focuses on reimagining druggability using chemoproteomic platforms to develop transformative medicines, particularly targeting the undruggable proteome. His group advances and applies chemoproteomic platforms to discover and pharmacologically target unique ligandable hotspots for disease therapy, with major research directions including covalent ligand discovery, targeted protein degradation technologies, and induced proximity-based therapeutic modalities.

Research topics

• Biology
• Biochemistry
• Chemistry
• Cell biology
• Computational biology
• Combinatorial chemistry
• Computer Science
• Medicine
• Cancer research
• Internal medicine
• Materials science
• Endocrinology
• Pharmacology
• Gerontology
• Nanotechnology
• Library science

Selected publications

• Methionine metabolism and the NOP2 methyltransferase are essential for MYC-Driven liver tumorigenesis

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-30

  articleOpen access

  Abstract Hepatocellular carcinoma (HCC) represents the third leading cause of cancer-related death worldwide and has been increasing in developed nations. 1,2 The MYC oncogene or its paralogs are frequently amplified or overexpressed in subtypes of cancer associated with stem cell-like features and worse clinical outcomes, 3,4 including in liver cancer. 5 Unfortunately, selective inhibitors that target MYC or its transcriptional program are not yet clinically available for therapy of HCC. Here, we identified methionine metabolism as a selective vulnerability for MYC but not RAS-driven liver cancers. MYC-driven liver cancer cells are methionine dependent, with markedly diminished tumor growth when mice are fed a methionine low diet. While RAS-driven liver cancer was resistant to a low methionine diet. S-adenosylmethionine (SAM), the predominant methyl donor, partially rescues cell proliferation following methionine depletion, suggesting that methylation processes are especially critical in the context of MYC high tumor cells. Heavy isotope methionine tracing in MYC high cells identified increased levels of m5C nucleotides. We found NOP2, an rRNA m5C-methyltransferase, was regulated by both MYC overexpression and methionine abundance linking the two processes. Methionine depletion reduced methylation of multiple 28S rRNA residues as did NOP2 knockdown. Depletion of NOP2 selectively inhibited MYC liver cancer cell proliferation and in vivo tumor growth. Thus, methionine catabolism is critical for MYC-driven liver tumorigenesis and the rRNA methyltransferase NOP2 may serve as a new therapeutic target in liver cancer.

  PublisherOA PDFDOI

• An Optimized RNF126-Targeting Covalent Handle for Molecular Glue Degraders

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-07 · 1 citations

  articleOpen accessSenior authorCorresponding

  Abstract Molecular glue degraders represent a powerful modality for targeting proteins that are refractory to traditional inhibition. However, rational design principles for molecular glue degraders remain poorly defined. Previously, we reported a chemistry-centric strategy to identify covalent degradative handles that, when appended to established ligands, convert non-degradative inhibitors into molecular glue degraders by engaging permissive E3 ligases. This effort identified a fumarate-based electrophilic handle that covalently modified the E3 ligase RNF126, enabling degradation of multiple protein targets when transplanted across diverse ligands. Despite its conceptual impact, the high intrinsic reactivity and cytotoxicity of the fumarate handle limited its translational utility. Here, we report the development of an optimized and metabolically stabilized RNF126-targeting covalent handle incorporating a trans -cyclobutane linker that exhibits reduced glutathione reactivity and diminished cytotoxicity while retaining robust degradative activity. When appended to the BET bromodomain inhibitor JQ1, this optimized handle yielded a potent and selective BRD4 degrader whose activity was dependent on RNF126. Importantly, transplantation of this handle onto a previously non-inhibitory ligand targeting the androgen receptor (AR) and its truncation variant, AR-V7, enabled selective degradation of both AR and AR-V7 in androgen-independent prostate cancer cells, thereby robustly inhibiting AR transcriptional activity beyond the established AR antagonist enzalutamide. Collectively, these findings demonstrate an optimized RNF126-based covalent handle for the rational development of molecular glue degraders against transcriptional regulators, including undruggable variants such as AR-V7.

  PublisherDOI

• Identification of acrylamide-based covalent inhibitors of SARS-CoV-2 (SCoV-2) Nsp15 using high-throughput screening and machine learning

  RSC Advances · 2025-01-01 · 1 citations

  articleOpen access

  <3, zero violations to Lipinski's rules, and no apparent pan-assay interference (PAINs) properties. In addition, based on this data as a training set, we developed an artificial intelligence (AI) model that accelerated the hit to lead process and had a 73% accuracy for predicting new acrylamide-based Nsp15 inhibitors. Collectively, these results demonstrate that acrylamide fragments have great potential for developing Nsp15 inhibitors.

  PublisherOA PDFDOI

• Induced ubiquitination bypasses canonical ERAD to drive ER protein degradation

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-01

  preprintOpen access

  ABSTRACT Heterobifunctional proteolysis-targeting chimeras (PROTACs) have emerged as a powerful strategy to degrade disease-relevant proteins, enabling targeting of previously “undruggable” proteins. Current degrader molecules primarily target cytosolic substrates, yet nearly one-third of the proteome resides in or transits the endoplasmic reticulum (ER), including receptors, secreted factors, and biosynthetic enzymes with high therapeutic relevance. Whether ER-localized proteins can be broadly targeted for induced degradation remains an open question. To address this gap, we employed a panel of fluorescent reporter cell lines and used the dTAG chemical-genetic system to recruit cytosolic E3 ligases. While lumenal substrates segregated from the cytosol were resistant to degradation, recruitment of cytosolic ligases effectively degraded ER membrane proteins across multiple topologies and with post-translational modifications. CRISPR genetic screens revealed that the induced degradation required the expected cullin RING ligase complexes but surprisingly bypassed ER-associated degradation (ERAD) machinery, with the exception of the AAA ATPase VCP. Mechanistic studies demonstrated that substrate ubiquitination was essential for VCP binding, and cleavage of ubiquitin chains released VCP, suggesting a model in which VCP directly extracts substrates independent of a dislocation apparatus. Extending this strategy to an endogenous substrate, we synthesized an HMGCR ERAD-TAC by linking atorvastatin to a cereblon E3 ligase recruiter and found that HMGCR degradation was likewise VCP-dependent. Together, these findings demonstrate that ER membrane proteins are generally susceptible to induced degradation via cytosolic ligase recruitment, uncovering a VCP-centered mechanism that operates independently of membrane-embedded ERAD machinery. This work establishes foundational principles for extending targeted protein degradation to the early secretory pathway. SIGNIFICANCE STATEMENT Targeted protein degradation has transformed drug discovery. Nearly one-third of the proteome reside in or transit the endoplasmic reticulum (ER), a compartment rich in therapeutically relevant but structurally complex targets. Whether these ER proteins can be broadly degraded using PROTACs has remained unknown. Here, we define the minimal requirements for degrading ER membrane proteins by recruiting cytosolic E3 ligases. Using chemical-genetic tools, genetic screens, and a statin-based degrader, we show that ubiquitination engages the VCP extraction machinery, enabling degradation of diverse ER membrane proteins independent of canonical ER-associated degradation components. These findings reveal a ubiquitin-driven route for membrane protein turnover, expand the landscape of druggable ER proteins, and establish principles for designing degraders operating in the early secretory pathway.

  PublisherOA PDFDOI

• Induced proximity-based therapeutic modalities

  Nature Reviews Drug Discovery · 2025-10-31 · 18 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Correction: Identification of acrylamide-based covalent inhibitors of SARS-CoV-2 (SCoV-2) Nsp15 using high-throughput screening and machine learning

  RSC Advances · 2025-01-01

  erratumOpen access

  Correction for ‘Identification of acrylamide-based covalent inhibitors of SARS-CoV-2 (SCoV-2) Nsp15 using high-throughput screening and machine learning’ by Teena Bajaj et al. , RSC Adv. , 2025, 15 , 10243–10256, https://doi.org/10.1039/D4RA06955B.

  PublisherOA PDFDOI

• A Vision for the Future of Molecular Cancer Therapeutics

  Molecular Cancer Therapeutics · 2025-05-02

  article1st authorCorresponding

  It is an incredible honor to serve as editor-in-chief of Molecular Cancer Therapeutics (MCT), following in the footsteps of esteemed leaders in the field, most recently Dr. Beverly A. Teicher. Under Dr. Teicher’s guidance, MCT has continued to thrive as a premier forum for groundbreaking research in cancer therapeutics. I would like to extend my deepest gratitude to Dr. Teicher for her dedication, leadership, and vision in advancing the journal’s mission.Since its inception in 2001, MCT has played a pivotal role in disseminating transformative discoveries, covering innovative cancer therapeutics, providing mechanistic insights into drug action, and developing novel targeted strategies. Over the past two decades, the landscape of cancer therapy has evolved dramatically, and we now stand at the precipice of a new era of therapeutic innovation.The expansion of next-generation therapeutic modalities in oncology has been revolutionary. Proteolysis-targeting chimeras and molecular glues redefine small-molecule drug discovery, whereas antibody–drug conjugates, bispecific antibodies, and immune checkpoint inhibitors continue transforming treatment paradigms. Cell-based therapies, including CAR-T cells and engineered immune effectors, have demonstrated unprecedented clinical success, and radiopharmaceuticals are opening new avenues for precision medicine. Vaccines, viral therapies, and gene therapies further expand our scope of approaches for tackling cancer. With these and other innovative, novel, and rapidly emerging modalities, alongside the discovery of novel cancer therapy targets, the need for a dedicated platform to showcase pioneering research has never been greater.As editor-in-chief, I envision making MCT the definitive journal for first disclosures of novel cancer therapeutics—whether small molecules, biologics, cell and gene therapies, or novel combination approaches. We aim to be the primary destination for studies presenting new drug structures, innovative preclinical models, mechanistic insights, and translational research that bridges the gap between discovery and clinical application. I also strive to make MCT a home for showcasing the discovery of novel therapeutic modalities and technologies for future cancer therapy. These areas of publishing will be alongside our historical areas of interest in the disclosure of preclinical studies of approved therapeutics, mechanism of action studies, mitigation of resistance, biomarkers of response, and applications of big data and artificial intelligence/machine learning in drug discovery.To achieve this, MCT will continue to uphold the highest standards of scientific rigor and impact, ensuring that the studies we publish advance the field and provide meaningful insights that inform clinical development. We welcome submissions that push the boundaries of what is possible in cancer treatment.I look forward to working with authors, our outstanding editorial board, dedicated reviewers, and the broader cancer research community to shape the future of MCT. Together, we will continue to foster innovation and accelerate the development of transformative cancer therapeutics. I invite you to join us in this mission and submit your most impactful work to Molecular Cancer Therapeutics—where the future of cancer treatment is being published.No disclosures were reported.

  PublisherDOI

• Tumor cell-adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis

  Nature Communications · 2025-08-20 · 5 citations

  articleOpen access

  A pro-tumorigenic role for adipocytes has been identified in breast cancer, and reliance on fatty acid catabolism found in aggressive tumors. The molecular mechanisms by which tumor cells coopt neighboring adipocytes, however, remain incompletely understood. Here, we describe a direct interaction linking tumorigenesis to adjacent adipocytes. We examine breast tumors and their normal adjacent tissue from several patient cohorts, patient-derived xenografts, and mouse models, and find that lipolysis and lipolytic signaling are activated in neighboring adipose tissue. We find that functional gap junctions form between breast cancer cells and adipocytes. As a result, cAMP is transferred from breast cancer cells to adipocytes and activates lipolysis in a gap junction-dependent manner. We find that connexin 31 (GJB3) promotes receptor triple negative breast cancer growth and activation of lipolysis in vivo. Thus, direct tumor cell-adipocyte interaction contributes to tumorigenesis and may serve as a new therapeutic target in breast cancer.

  PublisherOA PDFDOI

• Developmental Immunotoxicity of Low-dose Inorganic Arsenic Reprograms Macrophages Inducing Tumor-promoting Phenotypes

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-18

  preprintOpen access

  Abstract In many regions around the world, including the United States, inorganic arsenic (iAs) contaminates groundwater used for drinking, food production, and irrigation. Although the World Health Organization has set a safety limit of 10 µg/L for arsenic in drinking water, an estimated 200 million people worldwide are still exposed to arsenic concentrations above this threshold. Eliciting a broad range of adverse health effects, arsenic is a known carcinogen classified by the International Agency for Research on Cancer (IARC) and causes increased susceptibility to infectious diseases, highlighting its role as an immunotoxicant. The purpose of this study is to elucidate the effects of arsenic on the innate immune system, namely macrophages, using in vitro exposure models. Bone marrow-derived macrophages (BMDMs) were cultured from adult male and female C57/BL6 mice. These naïve macrophages (“M0” BMDMs) were exposed in vitro to a non-cytotoxic dose of iAs (0.1 µM sodium (meta)arsenite) during the 7 day period of macrophage differentiation and stimulated for 24 hrs with LPS and IFNγ (to induce “M1” pro-inflammatory activation) or IL-4 and IL-13 (to induce “M2” anti-inflammatory activation). In a parallel chronic exposure model, RAW 264.7 (RAW) macrophages were cultured in vitro with iAs for 70 days. Culture supernatant analysis for nitric oxide and cytokine secretion revealed sex-dependent differences in immune response between exposure models, as well as between iAs-exposed and nonexposed macrophages, with and without stimulation. Additionally, iAs-exposed macrophages exhibited increased lipid droplet formation and altered lipidomic and metabolomic profiles, as determined by LC/MS. Flow cytometric analysis further revealed changes in macrophage polarization markers in a sex- and stimulation-dependent manner, with M2-related markers being upregulated in iAs-exposed conditions. Finally, to assess the effects of iAs on macrophages in the context of cancer, we demonstrated that iAs-exposed macrophages displayed increased migration toward cancer cell-conditioned media, and promoted cancer cell proliferation. These results suggest that dysregulated macrophage polarization due to iAs exposure could impact susceptibility to diseases. This research contributes to our understanding of the full spectrum of adverse health effects of iAs exposure and may aid in the development of therapeutics for iAs-induced diseases, including cancer.

  PublisherOA PDFDOI

• Sulfinyl Aziridines as Stereoselective Covalent Destabilizing Degraders of the Oncogenic Transcription Factor MYC

  Angewandte Chemie International Edition · 2025-09-25 · 8 citations

  articleOpen accessSenior authorCorresponding

  Although MYC is a significant oncogenic transcription factor driver of cancer, directly targeting MYC has remained challenging due to its intrinsic disorder and poorly defined structure, deeming it "undruggable." Whether transient pockets formed within unstructured regions of proteins can be selectively targeted with small molecules remains an outstanding challenge. Here, we developed a stereochemically paired spirocyclic oxindole aziridine covalent library and screened this library for degradation of MYC. We identified a hit covalent ligand, KL2-236, bearing a unique sulfinyl aziridine warhead, that engaged MYC as a pure MYC/MAX protein complex, and in cancer cells to destabilize MYC, inhibit MYC transcriptional activity and degrade MYC in a proteasome-dependent manner through targeting intrinsically disordered C203 and D205 residues. Notably, this reactivity was most pronounced for specific stereoisomers of KL2-236 with a diastereomer, KL4-019, that was largely inactive. Mutagenesis of both C203 and D205 completely attenuated KL2-236-mediated MYC degradation. We also optimized our KL2-236 hit compound to generate a more potent, selective, and durable MYC degrader, KL4-219A. Our results reveal a novel ligandable site within MYC and indicate that certain intrinsically disordered regions within transcription factors, such as MYC, can be interrogated by isomerically unique chiral small molecules, leading to destabilization and degradation.

  PublisherOA PDFDOI

Recent grants

• Chemical Probes to Study Formaldehyde Biology

  NIH · $4.1M · 2017–2027

• Chemical Synthesis and Biology of Complex Alkaloids

  NIH · $2.0M · 2020–2024

• NIH Grant R00DA030908

  NIH · $723k · 2014

• NIH Grant R21CA170317

  NIH · $342k · 2014

• MFB: Developing Next-Generation Approaches to Targeted Protein Degradation

  NSF · $2.5M · 2021–2026

Frequent coauthors

• John A. Tallarico

  Novartis (United States)

  94 shared

• Markus Schirle

  Novartis (United States)

  93 shared

• Jeffrey M. McKenna

  Novartis (United States)

  89 shared

• Benjamin F. Cravatt

  Scripps Research Institute

  81 shared

• Mélanie Ott

  Gladstone Institutes

  78 shared

• Niren Murthy

  University of California, Berkeley

  73 shared

• Kamyar Behrouzi

  University of California, Berkeley

  69 shared

• Mohammad R. K. Mofrad

  University of California, Berkeley

  69 shared

Education

• Postdoc, Chemical Physiology

  Scripps Research Institute

  2011

• Ph.D., Molecular Toxicology

  University of California, Berkeley

  2008

• B.A., Molecular and Cell Biology

  University of California, Berkeley

  2003

Awards & honors

• Searle Scholar (2012)
• ACS Research Scholar Award (2014)
• The Mark Foundation for Cancer Research ASPIRE award (2019)
• National Cancer Institute Outstanding Investigator Award (20…