About

Darci J. Trader received her BS and MS degrees in chemistry from Southern Illinois University-Edwardsville in 2006 and 2007, respectively. She pursued her doctoral studies at Indiana University under the guidance of Professor Erin E. Carlson, where she developed a new chemoselective enrichment tagging protocol aimed at discovering natural products. After earning her PhD in 2013, she joined The Scripps Research Institute in Professor Tom Kodadek's laboratory, where she gained expertise in generating high-throughput screening (HTS) libraries and screening them for desired biological activities. Currently, Professor Trader leads her own laboratory focused on the development of drug-like molecules and chemical probes to monitor and perturb proteasome activity. Her research involves creating small molecule probes, stimulators, and inhibitors to study the roles of the standard proteasome and immunoproteasome in various diseases. Her lab's ongoing projects include medicinal chemistry and chemical biology studies aimed at developing new treatments for hematological cancers, proteasome stimulators to address neurological diseases associated with protein accumulation, and novel techniques to target immunoproteasome activity.

Research topics

• Computer Science
• Chemistry
• Biology
• Biochemistry
• Computational biology
• Machine Learning
• Artificial Intelligence
• Cell biology
• Combinatorial chemistry
• Neuroscience
• Genetics
• Bioinformatics
• Nanotechnology

Selected publications

• You are what you degrade: tracking the cellular fates of the proteasomal degradome

  Molecular Omics · 2026-01-01

  articleOpen accessSenior author

  The ubiquitin-proteasome system (UPS) is the primary protein degradation machinery in eukaryotic cells, composed of multiple proteasome isoforms. It plays critical roles in cellular proliferation, metabolism, immune regulation, oxidative stress, and aging, making it a long-standing focus of biological and therapeutic research. Recently, the UPS has been harnessed for the targeted degradation of disease-relevant proteins using proximity-inducing agents such as proteolysis-targeting chimeras and molecular glue degraders, which have transformed our understanding of druggability. Despite these advances, major gaps remain, particularly in understanding the proteasome's functional heterogeneity across biological contexts. Traditional research emphasizes proteasome structure, subunit function, and substrate features to guide chemical tool and therapeutic development. However, an often-overlooked aspect is the proteasomal degradome, the repertoire of peptide fragments generated during protein degradation. These peptides can exhibit biological activities distinct from their parent proteins, and pathogens, including viruses, have evolved mechanisms to block their production to evade immune detection. Thus, degradome characterization is essential to fully appreciate the proteasome's role in shaping cellular phenotypes in both healthy and diseased states. This review highlights recent studies exploring the degradome, with particular attention to -omic technologies applied to profile and interrogate these peptide products. By focusing on degradation outcomes rather than only the machinery, we aim to underscore the importance of tracing proteasome-derived peptides and their biological consequences. Ultimately, this perspective will broaden our understanding of the UPS while suggesting new avenues for therapeutic exploitation beyond current strategies.

  PublisherOA PDFDOI

• <i>In Vivo</i> Time-Lapse Imaging Reveals Differential Activity-Induced Regulation of Proteasome Activity in Subcellular Regions of the Optic Tectum in <i>Xenopus laevis</i> Tadpoles

  ACS Chemical Neuroscience · 2026-04-14

  articleOpen access

  The proteasome is a major organelle responsible for protein degradation in neurons and has been implicated in the regulation of signal transduction and activity-dependent plasticity mechanisms that are essential for normal neuronal function. However, our understanding of the regulation of proteasome activity in the brain is limited by the currently available assays and tools. Here, we used a fluorogenic substrate-based probe, TAS1, to directly monitor proteasome activity in the brain of Xenopus laevis tadpoles with time-lapse two-photon microscopy. With the spatial resolution enabled by in vivo imaging, our data revealed a significant difference in proteasome activity between brain regions enriched in neuronal soma versus neuropil under both basal and pharmacologically stimulated conditions, suggesting differential activity-induced regulation of proteasome activity across neuronal subcellular compartments. These results demonstrate the feasibility of using TAS1 to track proteasome activity in vivo and provide new evidence for the differential regulation of proteasome activity in different subcellular compartments of neurons in the intact neural circuit.

  PublisherDOI

• Increasing Proteasome Activity to Alter XBP1 Signaling of the UPR Pathway

  ChemBioChem · 2026-01-01 · 1 citations

  articleOpen accessSenior authorCorresponding

  Enhanced proteasome activity is known to confer resistance to cellular stress in vitro and in vivo, but such effects have largely been achieved through genetic upregulation of proteasome subunits and assembly factors. Here, we investigate whether small-molecule 20S proteasome activators can modulate XBP1 signaling during IRE1-driven unfolded protein response (UPR) activation. We show that pre-treatment with a 20S activator prior to IRE1 induction significantly attenuates XBP1 signaling, whereas treatment after chemical induction of IRE1 produces no detectable effect. These findings indicate that proteasome activators can bolster proteasome activity under endoplasmic reticulum (ER) stress, but their ability to modulate an ongoing UPR is limited. This work highlights a potential temporal window in which proteasome activation may influence stress-adaptive signaling.

  PublisherOA PDFDOI

• Synthesis and Application of BRD4‐Targeting ByeTACs (Bypassing E‐Ligase Targeting Chimeras)

  Current Protocols · 2025-08-01 · 1 citations

  articleSenior authorCorresponding

  Targeted protein degradation (TPD) has revolutionized the way we think of drug discovery and has the potential for substantial therapeutic benefits. Traditional mechanisms rely on taking advantage of the cells endogenous protein degradation pathway known as the ubiquitin proteasome system (UPS). Traditional proteolysis targeting chimeras (PROTACs) rely on this mechanism by developing heterobifunctional molecules, which are compounds that contain two different ligands that bind two different proteins linked together with varying linker lengths. These compounds typically contain a ligand to a protein of interest that is to be degraded and a linker to the other ligand that binds to an E3 ligase. Once these compounds bind both proteins of interest with the proper confirmation, the E-ligase complex can facilitate the ubiquitination of the protein, leading to its recognition by the proteasome for degradation. This approach has been effective at developing degraders for a wide variety of proteins, yet there remain several challenges, such as limited ligands to E3 ligases, selectivity, and degrading proteins that cannot be ubiquitinated. To overcome these limitations, we developed a new targeted protein degradation approach that can bypass the need for E3 ligases and ubiquitination that we have named ByeTACs. This was accomplished by developing a bifunctional molecule that recruits proteins directly to the 26S proteasome, no longer requiring the E ligase cascade. The protocols presented here describe the synthesis and application of a ByeTAC targeting bromodomain-containing protein 4 (BRD4), that can be generalized to other POIs to assess their "ByeTACability." © 2025 Wiley Periodicals LLC. Basic Protocol 1: Synthesis and characterization of a ByeTAC library targeting BRD4 Basic Protocol 2: Assessing degradation of BRD4 ByeTACs in cells Basic Protocol 3: Validating BRD4 ByeTACs mechanism of action.

  PublisherDOI

• NMR-Guided Studies to Establish the Binding Interaction between a Peptoid and Protein

  Journal of the American Chemical Society · 2025-07-15 · 2 citations

  articleOpen accessSenior authorCorresponding

  -substituted glycine monomers, into high-throughput screens can produce libraries of large structural diversity. Due to their malleable structures, peptoids can occupy unique protein binding sites, but determination of the peptoid binding pose is challenging. For example, the peptoid KDT-11 is reported to bind with low micromolar binding affinity to the proteasome subunit Rpn-13. Poor solubility of initial compound screening hits, like KDT-11, can greatly hinder progress in drug discovery since it limits in vitro characterization. The work reported here overcomes this hurdle with the addition of a solubility tag to KDT11, enabling elucidation of the biologically relevant surface of the peptoid through a variety of structure-activity relationships and biophysical studies. NMR paramagnetic relaxation data guided a structural modeling protocol using multiple molecular dynamics (MD) trajectories and extensive sampling. The final peptoid-protein structure is conformationally stable in equilibrium MD trajectories for >1 μs time period. KDT-11 binds across the β6/β7/β8 strands and α-helix of Rpn-13, revealing an interface for inhibition that could be targeted in future computational drug discovery efforts to obtain more potent ligands for Rpn-13. It is reasonable that the methodology described here can extend to other flexible peptoid or peptide ligands in complexes with proteins.

  PublisherOA PDFDOI

• Discovery of a First‐in‐Class Covalent Allosteric SHP1 Inhibitor with Immunotherapeutic Activity

  Angewandte Chemie International Edition · 2025-12-26 · 1 citations

  articleOpen access

  Abstract Src homology 2 domain‐containing phosphatase 1 (SHP1), encoded by PTPN6 , is a key intracellular mediator of inhibitory immune signals. SHP1 is garnering attention as a potential immunotherapeutic target since SHP1 deletion elicits strong antitumor activity by boosting both innate and adaptive immunity. Unfortunately, no quality SHP1 inhibitor exists to demonstrate its translatability owing to the challenges posed by the chemistry of the phosphatase active site. Herein, we describe the discovery of a first‐in‐class, phenyl chloroacetamide‐based covalent allosteric SHP1 inhibitor M029 through covalent fragment screening and multiparameter optimization. M029 inactivates SHP1 by covalently binding to a non‐conserved and cryptic Cys480 far away from the active site, thus uncovering a novel allosteric mechanism for SHP1 inhibition. In addition, M029 is highly selective for SHP1 and exhibits robust cellular target engagement. Importantly, M029 is orally active and blocks tumor progression in a syngeneic cancer model by activating natural killer cells and cytotoxic CD8 + T cells, along with reduced T cell exhaustion. Together, this study reveals a ligandable Cys that can be exploited for allosteric inhibition of SHP1, which has been refractory to targeted pharmacologic manipulation. The work also demonstrates small‐molecule SHP1 inhibition as a compelling approach for new cancer immunotherapy.

  PublisherDOI

• Oleanolic Acid Amide Derivatives as 20s Proteasome Stimulators

  ChemBioChem · 2025-09-19

  articleOpen accessSenior authorCorresponding

  Oleanolic acid (OA), a pentacyclic triterpenoid natural product, is previously identified as a proteasome stimulator using purified proteasome. Structure–activity relationship studies are carried out on OA at the C 28 and C 3 positions to determine if modifications at these positions can change proteasome stimulation activity. Ten amide derivatives are synthesized and tested in cells. These findings indicate that replacing the carboxylic acid with an amide at position C 28 does not diminish the stimulating effect, with certain functional groups making stimulation more potent. Amides with increased steric hinderance stimulate the proteasome the best, particularly amides with ortho substituted benzyl or isopropyl moieties. OA is further derivatized at the C 3 position by acylating the hydroxyl group. Changes at this position affect solubility of the derivatives, but do not dramatically diminish proteasome stimulation. These modifications highlight that the structure of OA can be modified to include linkers or covalent cross‐linking moieties to expand upon the available proteasome probes.

  PublisherOA PDFDOI

• Discovery of a First‐in‐Class Covalent Allosteric SHP1 Inhibitor with Immunotherapeutic Activity

  Angewandte Chemie · 2025-12-26

  articleOpen access

  Abstract Src homology 2 domain‐containing phosphatase 1 (SHP1), encoded by PTPN6 , is a key intracellular mediator of inhibitory immune signals. SHP1 is garnering attention as a potential immunotherapeutic target since SHP1 deletion elicits strong antitumor activity by boosting both innate and adaptive immunity. Unfortunately, no quality SHP1 inhibitor exists to demonstrate its translatability owing to the challenges posed by the chemistry of the phosphatase active site. Herein, we describe the discovery of a first‐in‐class, phenyl chloroacetamide‐based covalent allosteric SHP1 inhibitor M029 through covalent fragment screening and multiparameter optimization. M029 inactivates SHP1 by covalently binding to a non‐conserved and cryptic Cys480 far away from the active site, thus uncovering a novel allosteric mechanism for SHP1 inhibition. In addition, M029 is highly selective for SHP1 and exhibits robust cellular target engagement. Importantly, M029 is orally active and blocks tumor progression in a syngeneic cancer model by activating natural killer cells and cytotoxic CD8 + T cells, along with reduced T cell exhaustion. Together, this study reveals a ligandable Cys that can be exploited for allosteric inhibition of SHP1, which has been refractory to targeted pharmacologic manipulation. The work also demonstrates small‐molecule SHP1 inhibition as a compelling approach for new cancer immunotherapy.

  PublisherDOI

• Small molecule proteasome activation: comparative structural analysis of known stimulators

  Bioorganic & Medicinal Chemistry · 2025-11-06

  articleSenior authorCorresponding
  PublisherDOI

• Activation of the 20S proteasome core particle prevents cell death induced by oxygen- and glucose deprivation in cultured cortical neurons

  APOPTOSIS · 2025-03-17 · 1 citations

  articleOpen access

  Neuronal damage in brain ischemia is characterized by a disassembly of the proteasome and a decrease in its proteolytic activity. However, to what extent these alterations are coupled to neuronal death is controversial since proteasome inhibitors were shown to provide protection in different models of stroke in rodents. This question was addressed in the present work using cultured rat cerebrocortical neurons subjected to transient oxygen- and glucose-deprivation (OGD) as a model for in vitro ischemia. Under the latter conditions there was a time-dependent loss in the proteasome activity, determined by cleavage of the Suc-LLVY-AMC fluorogenic substrate, and the disassembly of the proteasome, as assessed by native-polyacrylamide gel electrophoresis followed by western blot against Psma2 and Rpt6, which are components of the catalytic core and regulatory particle, respectively. Immunocytochemistry experiments against the two proteins also showed differential effects on their dendritic distribution. OGD also downregulated the protein levels of Rpt3 and Rpt10, two components of the regulatory particle, by a mechanism dependent on the activity of NMDA receptors and mediated by calpains. Activation of the proteasome activity, using an inhibitor of USP14, a deubiquitinase enzyme, inhibited OGD-induced cell death, and decreased calpain activity as determined by analysis of spectrin cleavage. Similar results were obtained in the presence of two oleic amide derivatives (B12 and D3) which directly activate the 20S proteasome core particle. Together, these results show that proteasome activation prevents neuronal death in cortical neurons subjected to in vitro ischemia, indicating that inhibition of the proteasome is a mediator of neuronal death in brain ischemia.

  PublisherOA PDFDOI

Recent grants

• Discovery of Constrained Peptoid Oligomers for Novel Therapy of Multiple Myeloma

  NIH · $52k · 2014–2016

• Monitoring and Manipulating the Activity of the Immunoproteasome with Small Molecules

  NIH · $1.9M · 2020–2025

• Discovery of Constrained Peptoid Oligomers for Novel Therapy of Multiple Myeloma

  NIH · $50k · 2014–2017

• Development of Activity-Based Chemical Reporters to Differentiate Proteasome Isoforms in Cells

  NIH · $426k · 2019–2021

Frequent coauthors

• Breanna L. Zerfas

  Dana-Farber Cancer Institute

  15 shared

• Marianne E. Maresh

  Purdue University West Lafayette

  11 shared

• Rachel A. Coleman

  University of Maine

  10 shared

• Cody Loy

  University of California, Irvine

  8 shared

• Andres F. Salazar‐Chaparro

  Purdue University West Lafayette

  7 shared

• Erin E. Carlson

  7 shared

• Christine S. Muli

  Purdue University West Lafayette

  7 shared

• Kate A. Kragness

  Purdue University West Lafayette

  5 shared

Labs

• Darci Trader LabPI

  The lab is focused on the development of drug-like molecules and probes to monitor and perturb the activity of the proteasome.

Education

• Ph.D., Chemistry

  Indiana University

  2013