2. Academic Validation
  3. Chemical Proteomic Discovery of Isotype-Selective Covalent Inhibitors of the RNA Methyltransferase NSUN2

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

  • Angew Chem Int Ed Engl. 2023 Dec 18;62(51):e202311924. doi: 10.1002/anie.202311924.
Yongfeng Tao 1,  Jan G Felber 1 2,  Zhongyu Zou 3,  Evert Njomen 1,  Jarrett R Remsberg 1 4,  Daisuke Ogasawara 1,  Chang Ye 3,  Bruno Melillo 1 5,  Stuart L Schreiber 5 6,  Chuan He 3 7,  David Remillard 1 8,  Benjamin F Cravatt 1
Affiliations

Affiliations

  • 1 Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550N. Torrey Pines Road, La Jolla, CA-92307, USA.
  • 2 LMU Munich, Department of Pharmacy, Butenandtstr. 5-13, 81377, Munich, Germany.
  • 3 Department of Chemistry, The University of Chicago, 929 East 57th Street, GCIS E319B, Chicago, IL-60637, USA.
  • 4 Current address: Belharra Therapeutics, 3985 Sorrento Valley Blvd Suite C, San Diego, CA-92121, USA.
  • 5 Chemical Biology and Therapeutics Science Program, Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA-02142, USA.
  • 6 Harvard University, Department of Chemistry and Chemical Biology, 12 Oxford Street, MA-02138, Cambridge, USA.
  • 7 Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, GCIS E319B, Chicago, IL-60637, USA.
  • 8 Current address: Novartis, 10675 John Jay Hopkins Dr, San Diego, CA-92121, USA.
PMID: 37909922 DOI: 10.1002/anie.202311924
Abstract

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.

Keywords

5-Methylcytosine; Activity-Based Protein Profiling; Covalent Inhibitor; NSUN2; RNA Methylation.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-158301
    99.94%, NSUN2 Inhibitor