About

Christina M. Woo, Ph.D., is a Professor of Chemistry and Chemical Biology in the Department of Chemistry and Chemical Biology at Harvard University. She earned her B.S. from Wellesley College and completed her Ph.D. at Yale University under the mentorship of Seth Herzon. Following her doctoral studies, she pursued postdoctoral fellowships at the University of California, Berkeley, and Stanford University, working with Carolyn Bertozzi. Her research group, the Woo Lab, focuses on chemical biology, particularly in the area of targeted protein degradation and the study of small molecule interactions within the cellular proteome. The lab's work includes the development of molecular glue degraders for therapeutically relevant protein targets, with applications in hematologic and solid cancers, as well as exploring post-translational modifications in protein damage pathways and discovering optimal ligands for protein degradation. Professor Woo's research integrates chemical synthesis, proteomics, and chemical biology to advance understanding of protein function and regulation, aiming to translate these findings into innovative therapeutic strategies.

Research topics

• Chemistry
• Computer Science
• Data Mining
• Biochemistry
• Cell biology
• Engineering
• Biology
• Data science
• Combinatorial chemistry
• Organic chemistry
• Stereochemistry

Selected publications

• A method for the detection and enrichment of endogenous cereblon substrates

  Cell chemical biology · 2025-08-01 · 5 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Enzyme-Activated Sugar-Coated Bifunctional Degraders

  Journal of the American Chemical Society · 2025-09-12 · 13 citations

  articleSenior authorCorresponding

  Targeted protein degradation with compounds like proteolysis targeting chimeras (PROTACs) directs disease-associated proteins to the E3 ligase ubiquitin-proteasome system for removal. However, commonly employed E3 ligases such as cereblon (CRBN) are broadly expressed. To metabolically gate PROTAC activity, we developed an enzymatic activation strategy by integrating an O-GlcNAc modification to the cyclimids, ligands derived from the natural motifs recognized by CRBN. These sugar-coated PROTACs (SCPs) were designed using structural analyses of representative cyclimid degraders complexed with CRBN and target protein BRD4. We found that glycosylation of the cyclimid reduced CRBN binding and complex formation with BRD4 until enzymatic removal of the O-GlcNAc moiety by O-GlcNAcase (OGA). The requirement for enzymatic activation is demonstrated by in vitro biochemical binding, cellular degradation, and cell viability assays in engineered and native cell lines. O-GlcNAc is thus an effective mechanism to gate targeted protein degradation modalities that motivates the development of similar strategies to enhance selectivity with other protein modifications.

  PublisherDOI

• Targeted protein O-GlcNAc reveals transcriptional functions for O-GlcNAc

  Cell chemical biology · 2025-12-01 · 2 citations

  articleSenior author
  PublisherDOI

• A method for the detection and enrichment of endogenous cereblon substrates

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-26 · 1 citations

  preprintOpen accessSenior authorCorresponding

  C-Terminal cyclic imides are posttranslational modifications on proteins that are recognized and removed by the E3 ligase substrate adapter cereblon (CRBN). Despite the observation of these modifications across the proteome by mass spectrometry-based proteomics, an orthogonal and generalizable method to visualize the C-terminal cyclic imide would enhance detection, sensitivity, and throughput of endogenous CRBN substrate characterization. Here we develop an antibody-like reagent, termed "cerebody," for visualizing and enriching C-terminal cyclic imide-modified proteins. We describe the engineering of CRBN derivatives to produce cerebody and use it to identify CRBN substrates by Western blot and enrichment from whole cell and tissue lysates. CRBN substrates identified by cerebody enrichment are mapped, validated, and further characterized for dependence on the C-terminal cyclic imide modification. These methods will accelerate the characterization of endogenous CRBN substrates and their regulation.

  PublisherOA PDFDOI

• The contribution of cyclic imide stereoisomers on cereblon-dependent activity

  Chemical Science · 2025-01-01 · 4 citations

  articleOpen accessSenior authorCorresponding

  A systematic investigation of cyclic imide stereoisomers in small molecules, peptides, and proteins, examining their racemization, CRBN engagement, ternary complex formation in vitro , and resulting degradation outcomes in cells.

  PublisherOA PDFDOI

• PCMT1 generates the C-terminal cyclic imide degron on CRBN substrates

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-25 · 6 citations

  preprintOpen accessSenior authorCorresponding

  The E3 ligase substrate adapter cereblon (CRBN), the primary target of clinical agents thalidomide and lenalidomide, recognizes endogenous substrates bearing the C-terminal cyclic imide modification. Although C-terminal cyclic imides can form spontaneously, an enzyme that regulates the formation of these modifications and thereby promotes a biological pathway connecting substrates to CRBN is unknown. Here, we report that protein carboxymethyltransferase (PCMT1) promotes formation of the C-terminal cyclic imide on C-terminal asparagine residues of CRBN substrates. PCMT1 and CRBN co-regulate the levels of metabolic enzymes glutamine synthetase (GLUL) and inorganic pyrophosphatase 1 (PPA1) in vitro, in cells, and in vivo, and this regulation is associated with the proepileptic phenotype of CRBN knockout mouse models. The discovery of an enzyme that regulates CRBN substrates through the C-terminal cyclic imide modification reveals a previously unknown biological pathway that is perturbed by thalidomide derivatives and provides a biochemical basis for the connection between multiple biological processes and CRBN.

  PublisherOA PDFDOI

• Investigation of Glutarimide <i>N</i>-Alkylated Derivatives of Lenalidomide

  ACS Chemical Biology · 2025-06-16

  articleSenior authorCorresponding

  Lenalidomide is a thalidomide derivative that engages the E3 ligase substrate receptor cereblon (CRBN) to promote targeted protein degradation. Lenalidomide possesses a glutarimide moiety, which is responsible for CRBN engagement, and an isoindoline moiety, which promotes neosubstrate recruitment. Modification of the glutarimide is a generalizable prodrug strategy to inhibit CRBN binding for the selective activation of CRBN-dependent activity, yet these compounds may possess CRBN-independent effects. We prepared six N-alkylated glutarimide derivatives and found CRBN-independent effects on TNFα inhibition and selective effects in the cell viability profiles. Evaluation of selected compounds by global proteomics in KG1a cells reveals that the downregulation of Rab28 is CRBN-independent and mediated by autophagy. Finally, we developed a representative prodrug to demonstrate the enzymatic release of lenalidomide. Collectively, although some CRBN-independent properties are observed, modification of glutarimide is a generally viable strategy to prevent CRBN engagement in a prodrug strategy.

  PublisherDOI

• Probing the E3 Ligase Adapter Cereblon with Chemical Biology

  Accounts of Chemical Research · 2025-04-01 · 3 citations

  articleSenior authorCorresponding

  The E3 ligase substrate adapter cereblon (CRBN) has garnered widespread interest from the research laboratory to the clinic. CRBN was first discovered for its association with neurological development and subsequently identified as the target of thalidomide and lenalidomide, therapeutic agents used in the treatment of hematopoietic malignancies. Both thalidomide and lenalidomide have been repurposed as ligands for targeted protein degradation therapeutic modalities. These agents were proposed to mimic a naturally occurring ligand, although the native substrate recognition mechanism of CRBN remained elusive. Chemical biology, which involves the use of chemical tools to modulate and probe biological systems, can provide unique insights into the molecular mechanisms and interactions of proteins with their cognate ligands. Here we describe our use of chemical biology approaches, including photoaffinity labeling, chemical proteomics, and targeted protein degradation, to interrogate the biological activities of CRBN in the presence or absence of its ligands. Our development of a photoaffinity labeling probe derived from lenalidomide, termed photolenalidomide, enabled mapping of the binding site on CRBN and identification of a new target recruited to CRBN by lenalidomide through chemical proteomics. Further derivatization of the lenalidomide scaffold afforded DEG-77, a potent degrader with therapeutic efficacy against acute myeloid leukemia. Our parallel development of chemically defined probes that are inspired by heterobifunctional targeted protein degradation agents and functionally engage CRBN in cells revealed that thalidomide is a peptidomimetic of an underappreciated protein modification termed the C-terminal cyclic imide, which arises from intramolecular cyclization of asparagine or glutamine residues and represents a degron endogenously recognized by CRBN. Protein engineering and proteomic efforts validated the CRBN-dependent regulation of proteins bearing the C-terminal cyclic imide modification in vitro and in cells and the prevalence of the C-terminal cyclic imide in the biological system. Application of C-terminal cyclic imides as a class of cyclimid ligands for targeted protein degradation led to the development of a variety of heterobifunctional degraders with distinct efficacy and target selectivity, whereas examination of the occurrence of C-terminal cyclic imides as a form of protein damage uncovered the intrinsic and extrinsic factors that predispose peptides and proteins to C-terminal cyclic imide formation and the role of CRBN in mitigating the accumulation of damaged proteins with a propensity for aggregation. Future investigation of C-terminal cyclic imides, synthetic ligands, and their relationship to CRBN biology will illuminate regulatory mechanisms that are controlled by CRBN and drive the pursuit of additional functional chemistries on proteins and the biological pathways that intercept them.

  PublisherDOI

• Durotaxis is a driver and potential therapeutic target in lung fibrosis and metastatic pancreatic cancer

  Nature Cell Biology · 2025-09-01 · 14 citations

  articleOpen access

  Abstract Durotaxis, cell migration along stiffness gradients, is linked to embryonic development, tissue repair and disease. Despite solid in vitro evidence, its role in vivo remains largely speculative. Here we demonstrate that durotaxis actively drives disease progression in vivo in mouse models of lung fibrosis and metastatic pancreatic cancer. In lung fibrosis, durotaxis directs fibroblast recruitment to sites of injury, where they undergo mechano-activation into scar-forming myofibroblasts. In pancreatic cancer, stiffening of the tumour microenvironment induces durotaxis of cancer cells, promoting metastatic dissemination. Mechanistically, durotaxis is mediated by focal adhesion kinase (FAK)–paxillin interaction, a mechanosensory module that links stiffness cues to transcriptional programmes via YAP signalling. To probe this genetically, we generated a FAK-FAT L994E knock-in mouse, which disrupts FAK–paxillin binding, blocks durotaxis and attenuates disease severity. Pharmacological inhibition of FAK–paxillin interaction with the small molecule JP-153 mimics these effects. Our findings establish durotaxis as a disease mechanism in vivo and support anti-durotactic therapy as a potential strategy for treating fibrosis and cancer.

  PublisherDOI

• PCMT1 generates the C-terminal cyclic imide degron on CRBN substrates

  Nature Chemical Biology · 2025-12-29 · 3 citations

  articleSenior author
  PublisherDOI

Recent grants

• Tools to facilitate manipulation of protein-specific glycosylation stoichiometry in cells

  NIH · $928k · 2019–2022

• Writing and erasing O-GlcNAc on target proteins in the brain

  NIH · $1.8M · 2023–2026

• Precision pharmacology of the opioids

  NIH · $2.5M · 2018–2024

• Uncovering the substrate recognition mechanisms of the E3 ligase adaptor cereblon

  NIH · $1.3M · 2022–2026

• Tools to facilitate manipulation of protein-specific glycosylation stoichiometry in cells

  NIH · $495k · 2019–2022

Frequent coauthors

• Carolyn R. Bertozzi

  Stanford University

  37 shared

• Alejandra Felix

  Dana-Farber Cancer Institute

  26 shared

• Anthony T. Iavarone

  QB3

  26 shared

• Sharon J. Pitteri

  Stanford University

  26 shared

• William E. Byrd

  25 shared

• Parastoo Azadi

  University of Georgia

  25 shared

• Devon K. Zuegel

  University of Georgia

  25 shared

• Mayumi Ishihara

  University of Georgia

  25 shared

Labs

• Woo GroupPI

Awards & honors

• Burroughs Wellcome Fund CASI fellowship (2015)
• Jane Coffin Childs postdoctoral fellowship at University of…