About

Dustin J. Maly, Ph.D., is the Principal Investigator and Raymon E. and Rosellen M. Lawton Endowed Professor of Chemistry at the University of Washington, Seattle, Department of Chemistry. His research focuses on using organic synthesis to generate small molecules aimed at controlling the growth of prostate cancers. Additionally, he employs chemical proteomics techniques to identify the molecular targets of these small molecules. This integrated approach combines synthetic chemistry and proteomic analysis to advance understanding and potential therapeutic strategies for prostate cancer. Outside of his professional work, Professor Maly enjoys reading, driving, and traveling.

Research topics

• Biology
• Computational biology
• Genetics
• Pharmacology
• Cell biology
• Computer Science
• Internal medicine
• Medicine
• Immunology
• Bioinformatics
• Microbiology
• Virology
• Cancer research

Selected publications

• Activity Assay v2

  2026-02-24

  articleOpen accessSenior author

  This SOP describes the procedure for performing the LABEL-seq MAPK signaling activity assay using a tdMCP-Erk2 phosphorylation reporter to quantify intracellular BRaf variant activity in a pooled format.

  PublisherOA PDFDOI

• MEK interactions tune RAF kinase sensitivity to conformation-selective inhibition

  Nature Chemical Biology · 2026-05-12

  articleOpen accessSenior author

  RAF kinases are key effectors in the RAS-RAF-MEK-ERK signaling pathway, making them important targets for the development of cancer therapeutics. Here we investigate the variable potency of DFG-out-stabilizing RAF inhibitors in mutant KRAS-expressing cell lines. We demonstrate that inhibitor potency correlates with basal RAF activity, with more active RAF being more sensitive to inhibition. We further show that DFG-out-stabilizing inhibitors disrupt high-affinity RAF-MEK interactions, promoting the formation of inhibited RAF dimers. Furthermore, we identify cobimetinib as an MEK inhibitor that uniquely sensitizes RAF kinases to DFG-out-stabilizing inhibitors by disrupting autoinhibited RAF-MEK complexes. Building on this insight, we developed cobimetinib analogs with enhanced sensitization properties. Together, our findings provide a mechanistic framework for understanding the cellular determinants of DFG-out-stabilizing inhibitor sensitivity and offer strategies for optimizing synergistic RAF-MEK inhibitor combinations.

  PublisherDOI

• Variant Abundance Assay v2

  2026-02-24

  articleOpen accessSenior author

  Quantify intracellular abundance of pooled tdMCP-tagged protein variants via ratiometric sequencing of MS2-circRNA barcodes co-enriched in parallel Flag (variant) and Myc (tdMCP standard) immunoprecipitations.

  PublisherOA PDFDOI

• Identification of affinity-optimized peptide binders of a viral protease for chemical genetic applications

  Bioorganic & Medicinal Chemistry Letters · 2025-11-05

  articleSenior authorCorresponding
  PublisherDOI

• Pharmacologic inhibition of IRE1α-dependent decay protects alveolar epithelial identity and prevents pulmonary fibrosis in mice

  Journal of Clinical Investigation · 2025-10-14 · 3 citations

  articleOpen access

  Stress-induced epithelial plasticity is central to lung regeneration, fibrosis, and malignancy, but how cellular stress leads to differentiation is incompletely understood. Here, we found a central role for IRE1α, a conserved mediator of the unfolded protein response (UPR), in stimulating the plasticity of alveolar type 2 (AT2) cells. In single-cell RNA-seq, IRE1α activity was associated with loss of AT2 identity and progression toward a damage-associated transitional state unique to fibrosis. AT2 plasticity required destructive regulated IRE1α-dependent decay (RIDD), which we demonstrated by deploying PAIR2, a kinase modulator that inhibits RIDD while preserving IRE1α's adaptive XBP1 mRNA splicing activity. In vivo, selective inhibition of RIDD with PAIR2 reduced AT2 differentiation into profibrotic transitional cells and protected mice from bleomycin-induced pulmonary fibrosis. Mechanistically, we identified the Fgfr2 mRNA as a direct and regulated substrate for IRE1α's RNase in primary AT2 cells and in a biochemically reconstituted cell-free system. Loss of Fgf signaling caused AT2 differentiation, while gain of signaling protected cells from IRE1α-induced differentiation. We propose that IRE1α downregulates Fgf signaling through RIDD, provoking loss of AT2 identity and differentiation towards a profibrotic phenotype. Thus, IRE1α's RIDD activity emerges as a novel target for treatment of pulmonary fibrosis and potentially other diseases driven by aberrant epithelial cell plasticity.

  PublisherDOI

• Multiplex design and discovery of proximity handles for programmable proteome editing

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-13 · 2 citations

  preprintOpen access

  ABSTRACT Although we now have a rich toolset for genome editing, an equivalent framework for manipulating the proteome with a comparable flexibility and specificity remains elusive. A promising strategy for “proteome editing” is to use bifunctional molecules ( e.g. PROteolysis-Targeting Chimeras or PROTACs 1 ) that bring a target protein into proximity with a degradation or stabilization effector, but their broader application is constrained by a limited repertoire of well-characterized target or effector “handles”. We asked whether coupling de novo protein design to a multiplex screening framework could address this gap by accelerating the discovery of effector handles for intracellular protein degradation, stabilization, or relocalization. Using LABEL-seq 2 , a sequencing-based assay that enables multiplex, quantitative measurement of protein abundance, we screened 9,715 de novo designed candidate effector handles for their ability to recruit a target protein to components of the ubiquitin–proteasome system 3 (UPS) (FBXL12, TRAF2, UCHL1, USP38) or the autophagy pathway 4 (GABARAP, GABARAPL2, MAP1LC3A). In a single experiment, we discovered hundreds of de novo designed effector handles that reproducibly drove either intracellular degradation (n = 277) or stabilization (n = 204) of a reporter protein. Validation of a subset of these hits in an orthogonal assay confirmed that sequencing-based measurements from the primary screen reliably reflected changes in intracellular abundance of the target protein. Successful effector handles were discovered for both the UPS (n = 194) and autophagy (n = 287) pathways, which provide complementary routes for programmable proteome editing. Autophagy-recruiting effector handles generalized to endogenous targets, as substituting the reporter-specific target handle with a high-affinity MCL1 binder 5 reduced endogenous levels of this intracellular oncoprotein 6 . Moreover, directing autophagy-recruiting effector handles to the outer mitochondrial membrane dramatically perturbed mitochondrial networks in a manner consistent with synthetic tethering and sequestration 7,8 . Beyond generating a diverse repertoire of protein abundance or localization effector handles, our results establish a scalable, low-cost platform that links deep learning–guided protein design to functional cellular readouts, and chart a course toward a general framework for programmable proteome editing.

  PublisherOA PDFDOI

• Figure S12 from A Compound That Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer

  2024-07-05

  preprintOpen access

  <p>Figure S12 shows antiproliferative activity of BKIDCs on HK1 and HK2 KO LNCaP cell lines.</p>

  PublisherDOI

• Figure S7 from A Compound That Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer

  2024-07-05

  preprintOpen access

  <p>Figure S7 shows Western blot analysis confirming the findings with RPPA.</p>

  PublisherDOI

• Figure S7 from A Compound That Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer

  2024-07-05

  preprintOpen access

  <p>Figure S7 shows Western blot analysis confirming the findings with RPPA.</p>

  PublisherOA PDFDOI

• Table S7 from A Compound That Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer

  2024-07-05

  preprintOpen access

  <p>Table S7 shows pharmacokinetic parameters after a single dose in mouse, rat, dog, and cynomolgus monkey.</p>

  PublisherDOI

Recent grants

• Target identification by small-molecule labeling in live cells

  NIH · $425k · 2014–2017

• Discovery and validation of new kinase drug targets in T. brucei

  NIH · $1.6M · 2014–2019

• New Molecular Probes For Protein Kinases

  NIH · $5.5M · 2008–2027

• Kinase Profiling with Quantititative Chemoproteomics

  NIH · $665k · 2013–2017

• Chemical Genetic Analysis of RAS Signaling

  NIH · $1.5M · 2022–2026

Frequent coauthors

• Kayode K. Ojo

  151 shared

• Wesley C. Van Voorhis

  149 shared

• Ryan Choi

  130 shared

• B. Gayani K. Perera

  128 shared

• Lynn K. Barrett

  125 shared

• Matthew A. Hulverson

  125 shared

• Grant R. Whitman

  117 shared

• Samuel L.M. Arnold

  University of Washington

  114 shared

Labs

• Maly LabPI