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Journal Article Nature chemical biology · October 2025 The stimulator of interferon genes (STING) innate immune pathway can exacerbate inflammatory diseases when aberrantly activated, emphasizing an unmet need for STING antagonists. However, no inhibitors have advanced to the clinic because it remains unclear ... Full text Cite

Chemical tools to expand the ligandable proteome: Diversity-oriented synthesis-based photoreactive stereoprobes.

Journal Article Cell chemical biology · December 2024 Chemical proteomics enables the global analysis of small molecule-protein interactions in native biological systems and has emerged as a versatile approach for ligand discovery. The range of small molecules explored by chemical proteomics has, however, rem ... Full text Cite

Redirecting the pioneering function of FOXA1 with covalent small molecules.

Journal Article Molecular cell · November 2024 Pioneer transcription factors (TFs) bind to and open closed chromatin, facilitating engagement by other regulatory factors involved in gene activation or repression. Chemical probes are lacking for pioneer TFs, which has hindered their mechanistic investig ... Full text Cite

Multi-tiered chemical proteomic maps of tryptoline acrylamide-protein interactions in cancer cells.

Journal Article Nature chemistry · October 2024 Covalent chemistry is a versatile approach for expanding the ligandability of the human proteome. Activity-based protein profiling (ABPP) can infer the specific residues modified by electrophilic compounds through competition with broadly reactive probes. ... Full text Cite

Proteomic Ligandability Maps of Spirocycle Acrylamide Stereoprobes Identify Covalent ERCC3 Degraders.

Journal Article Journal of the American Chemical Society · April 2024 Covalent chemistry coupled with activity-based protein profiling (ABPP) offers a versatile way to discover ligands for proteins in native biological systems. Here, we describe a set of stereo- and regiochemically defined spirocycle acrylamides and the anal ... Full text Cite

Covalent Targeting As a Common Mechanism for Inhibiting NLRP3 Inflammasome Assembly.

Journal Article ACS chemical biology · February 2024 The NLRP3 inflammasome is a cytosolic protein complex important for the regulation and secretion of inflammatory cytokines, including IL-1β and IL-18. Aberrant overactivation of NLRP3 is implicated in numerous inflammatory disorders. However, the activatio ... Full text Cite

Chemical Proteomic Discovery of Isotype-Selective Covalent Inhibitors of the RNA Methyltransferase NSUN2.

Journal Article Angewandte Chemie (International ed. in English) · December 2023 5-Methylcytosine (m5 C) is an RNA modification prevalent on tRNAs, where it can protect tRNAs from endonucleolytic cleavage to maintain protein synthesis. The NSUN family (NSUN1-7 in humans) of RNA methyltransferases are capable of installing th ... Full text Cite

Assigning functionality to cysteines by base editing of cancer dependency genes.

Journal Article Nature chemical biology · November 2023 Covalent chemistry represents an attractive strategy for expanding the ligandability of the proteome, and chemical proteomics has revealed numerous electrophile-reactive cysteines on diverse human proteins. Determining which of these covalent binding event ... Full text Cite

Development of a Cell-Based AlphaLISA Assay for High-Throughput Screening for Small Molecule Proteasome Modulators

Journal Article ACS Omega · May 2, 2023 The balance between protein degradation and protein synthesis is a highly choreographed process generally called proteostasis. Most intracellular protein degradation occurs through the ubiquitin-proteasome system (UPS). This degradation takes place through ... Full text Cite

Proteomic discovery of chemical probes that perturb protein complexes in human cells.

Journal Article Molecular cell · May 2023 Most human proteins lack chemical probes, and several large-scale and generalizable small-molecule binding assays have been introduced to address this problem. How compounds discovered in such "binding-first" assays affect protein function, nonetheless, of ... Full text Cite

Selective inhibitors of SARM1 targeting an allosteric cysteine in the autoregulatory ARM domain.

Journal Article Proceedings of the National Academy of Sciences of the United States of America · August 2022 The nicotinamide adenine dinucleotide hydrolase (NADase) sterile alpha toll/interleukin receptor motif containing-1 (SARM1) acts as a central executioner of programmed axon death and is a possible therapeutic target for neurodegenerative disorders. While o ... Full text Cite

Small Molecule 20S Proteasome Enhancer Regulates MYC Protein Stability and Exhibits Antitumor Activity in Multiple Myeloma

Journal Article Biomedicines · May 1, 2022 Despite the addition of several new agents to the armamentarium for the treatment of multiple myeloma (MM) in the last decade and improvements in outcomes, the refractory and relapsing disease continues to take a great toll, limiting overall survival. Ther ... Full text Cite

Regulation of Autophagic Flux by the 20S Proteasome.

Journal Article Cell chemical biology · September 2019 The proteolytic arm of the protein homeostasis network is maintained by both the ubiquitin-proteasome system (UPS) and autophagy. A well-balanced crosstalk between the two catabolic pathways ensures energy-efficient maintenance of cellular function. Our cu ... Full text Cite

Proteasome Activation as a New Therapeutic Approach To Target Proteotoxic Disorders.

Journal Article Journal of medicinal chemistry · July 2019 Proteasomes are multienzyme complexes that maintain protein homeostasis (proteostasis) and important cellular functions through the degradation of misfolded, redundant, and damaged proteins. It is well established that aging is associated with the accumula ... Full text Cite

Small Molecule Modulation of Proteasome Assembly.

Journal Article Biochemistry · July 2018 The 20S proteasome is the main protease that directly targets intrinsically disordered proteins (IDPs) for proteolytic degradation. Mutations, oxidative stress, or aging can induce the buildup of IDPs resulting in incorrect signaling or aggregation, associ ... Full text Cite

Small Molecule Enhancement of 20S Proteasome Activity Targets Intrinsically Disordered Proteins.

Journal Article ACS chemical biology · September 2017 The 20S proteasome is the main protease for the degradation of oxidatively damaged and intrinsically disordered proteins. When accumulation of disordered or oxidatively damaged proteins exceeds proper clearance in neurons, imbalanced pathway signaling or a ... Full text Cite

Humanin Peptide Binds to Insulin-Like Growth Factor-Binding Protein 3 (IGFBP3) and Regulates Its Interaction with Importin-β.

Journal Article Protein and peptide letters · January 2015 Nuclear translocation of IGFBP3 by importin-β1 is a prerequisite for IGFBP3-induced apoptosis. The neuroprotective peptide humanin (HN) counteracts IGFBP3-induced cell death. However, the mechanism by which humanin protects cells is currently unknown. The ... Full text Cite