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Chemical Proteomic Discovery of Isotype-Selective Covalent Inhibitors of the RNA Methyltransferase NSUN2.
Tao, Yongfeng; Felber, Jan G; Zou, Zhongyu; Njomen, Evert; Remsberg, Jarrett R; Ogasawara, Daisuke; Ye, Chang; Melillo, Bruno; Schreiber, Stuart L; He, Chuan; Remillard, David; Cravatt, Benjamin F.
Afiliación
  • Tao Y; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550N. Torrey Pines Road, La Jolla, CA-92307, USA.
  • Felber JG; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550N. Torrey Pines Road, La Jolla, CA-92307, USA.
  • Zou Z; LMU Munich, Department of Pharmacy, Butenandtstr. 5-13, 81377, Munich, Germany.
  • Njomen E; Department of Chemistry, The University of Chicago, 929 East 57th Street, GCIS E319B, Chicago, IL-60637, USA.
  • Remsberg JR; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550N. Torrey Pines Road, La Jolla, CA-92307, USA.
  • Ogasawara D; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550N. Torrey Pines Road, La Jolla, CA-92307, USA.
  • Ye C; Current address: Belharra Therapeutics, 3985 Sorrento Valley Blvd Suite C, San Diego, CA-92121, USA.
  • Melillo B; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550N. Torrey Pines Road, La Jolla, CA-92307, USA.
  • Schreiber SL; Department of Chemistry, The University of Chicago, 929 East 57th Street, GCIS E319B, Chicago, IL-60637, USA.
  • He C; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550N. Torrey Pines Road, La Jolla, CA-92307, USA.
  • Remillard D; Chemical Biology and Therapeutics Science Program, Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA-02142, USA.
  • Cravatt BF; Chemical Biology and Therapeutics Science Program, Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA-02142, USA.
Angew Chem Int Ed Engl ; 62(51): e202311924, 2023 Dec 18.
Article en En | MEDLINE | ID: mdl-37909922
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 the methyl group onto the C5 position of cytosines in RNA. NSUNs are implicated in a wide range of (patho)physiological processes, but selective and cell-active inhibitors of these enzymes are lacking. Here, we use cysteine-directed activity-based protein profiling (ABPP) to discover azetidine acrylamides that act as stereoselective covalent inhibitors of human NSUN2. Despite targeting a conserved catalytic cysteine in the NSUN family, the NSUN2 inhibitors show negligible cross-reactivity with other human NSUNs and exhibit good proteome-wide selectivity. We verify that the azetidine acrylamides inhibit the catalytic activity of recombinant NSUN2, but not NSUN6, and demonstrate that these compounds stereoselectively disrupt NSUN2-tRNA interactions in cancer cells, leading to a global reduction in tRNA m5 C content. Our findings thus highlight the potential to create isotype-selective and cell-active inhibitors of NSUN2 with covalent chemistry targeting a conserved catalytic cysteine.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ARNt Metiltransferasas / Azetidinas / Inhibidores Enzimáticos / Metiltransferasas Límite: Humans Idioma: En Revista: Angew Chem Int Ed Engl Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ARNt Metiltransferasas / Azetidinas / Inhibidores Enzimáticos / Metiltransferasas Límite: Humans Idioma: En Revista: Angew Chem Int Ed Engl Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Alemania