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Chemoproteomics Identifies State-Dependent and Proteoform-Selective Caspase-2 Inhibitors.
Castellón, José O; Ofori, Samuel; Burton, Nikolas R; Julio, Ashley R; Turmon, Alexandra C; Armenta, Ernest; Sandoval, Carina; Boatner, Lisa M; Takayoshi, Evan E; Faragalla, Marina; Taylor, Cameron; Zhou, Ann L; Tran, Ky; Shek, Jeremy; Yan, Tianyang; Desai, Heta S; Fregoso, Oliver I; Damoiseaux, Robert; Backus, Keriann M.
Afiliación
  • Castellón JO; Biological Chemistry Department, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, United States.
  • Ofori S; Biological Chemistry Department, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, United States.
  • Burton NR; Biological Chemistry Department, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, United States.
  • Julio AR; Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095, United States.
  • Turmon AC; Biological Chemistry Department, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, United States.
  • Armenta E; Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095, United States.
  • Sandoval C; Biological Chemistry Department, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, United States.
  • Boatner LM; Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095, United States.
  • Takayoshi EE; Biological Chemistry Department, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, United States.
  • Faragalla M; Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095, United States.
  • Taylor C; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California 90095, United States.
  • Zhou AL; Biological Chemistry Department, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, United States.
  • Tran K; Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095, United States.
  • Shek J; Biological Chemistry Department, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, United States.
  • Yan T; Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095, United States.
  • Desai HS; Biological Chemistry Department, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, United States.
  • Fregoso OI; Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095, United States.
  • Damoiseaux R; California NanoSystems Institute (CNSI), UCLA, Los Angeles, California 90095, United States.
  • Backus KM; Biological Chemistry Department, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, United States.
J Am Chem Soc ; 146(22): 14972-14988, 2024 Jun 05.
Article en En | MEDLINE | ID: mdl-38787738
ABSTRACT
Caspases are a highly conserved family of cysteine-aspartyl proteases known for their essential roles in regulating apoptosis, inflammation, cell differentiation, and proliferation. Complementary to genetic approaches, small-molecule probes have emerged as useful tools for modulating caspase activity. However, due to the high sequence and structure homology of all 12 human caspases, achieving selectivity remains a central challenge for caspase-directed small-molecule inhibitor development efforts. Here, using mass spectrometry-based chemoproteomics, we first identify a highly reactive noncatalytic cysteine that is unique to caspase-2. By combining both gel-based activity-based protein profiling (ABPP) and a tobacco etch virus (TEV) protease activation assay, we then identify covalent lead compounds that react preferentially with this cysteine and afford a complete blockade of caspase-2 activity. Inhibitory activity is restricted to the zymogen or precursor form of monomeric caspase-2. Focused analogue synthesis combined with chemoproteomic target engagement analysis in cellular lysates and in cells yielded both pan-caspase-reactive molecules and caspase-2 selective lead compounds together with a structurally matched inactive control. Application of this focused set of tool compounds to stratify the functions of the zymogen and partially processed (p32) forms of caspase-2 provide evidence to support that caspase-2-mediated response to DNA damage is largely driven by the partially processed p32 form of the enzyme. More broadly, our study highlights future opportunities for the development of proteoform-selective caspase inhibitors that target nonconserved and noncatalytic cysteine residues.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteómica / Caspasa 2 / Inhibidores de Caspasas Límite: Humans Idioma: En Revista: J Am Chem Soc Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteómica / Caspasa 2 / Inhibidores de Caspasas Límite: Humans Idioma: En Revista: J Am Chem Soc Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos