دورية أكاديمية
Chemoproteomics-enabled discovery of a covalent molecular glue degrader targeting NF-κB.
| العنوان: | Chemoproteomics-enabled discovery of a covalent molecular glue degrader targeting NF-κB. |
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| المؤلفون: | King EA; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720, USA; Innovative Genomics Institute, Berkeley, CA 94704, USA., Cho Y; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720, USA; Innovative Genomics Institute, Berkeley, CA 94704, USA., Hsu NS; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720, USA; Innovative Genomics Institute, Berkeley, CA 94704, USA., Dovala D; Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720, USA; Novartis Institutes for BioMedical Research, Emeryville, CA 94608, USA., McKenna JM; Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720, USA; Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA., Tallarico JA; Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720, USA; Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA., Schirle M; Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720, USA; Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA., Nomura DK; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA; Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA 94720, USA; Innovative Genomics Institute, Berkeley, CA 94704, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: dnomura@berkeley.edu. |
| المصدر: | Cell chemical biology [Cell Chem Biol] 2023 Apr 20; Vol. 30 (4), pp. 394-402.e9. Date of Electronic Publication: 2023 Mar 09. |
| نوع المنشور: | Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 101676030 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2451-9448 (Electronic) Linking ISSN: 24519448 NLM ISO Abbreviation: Cell Chem Biol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Cambridge, MA : Cell Press, 2016- |
| مواضيع طبية MeSH: | NF-kappa B*/metabolism , Proteomics*, Ligands ; Proteolysis ; Proteasome Endopeptidase Complex/metabolism ; Ubiquitin-Protein Ligases/metabolism |
| مستخلص: | Targeted protein degradation has arisen as a powerful therapeutic modality for degrading disease targets. While proteolysis-targeting chimera (PROTAC) design is more modular, the discovery of molecular glue degraders has been more challenging. Here, we have coupled the phenotypic screening of a covalent ligand library with chemoproteomic approaches to rapidly discover a covalent molecular glue degrader and associated mechanisms. We have identified a cysteine-reactive covalent ligand EN450 that impairs leukemia cell viability in a NEDDylation and proteasome-dependent manner. Chemoproteomic profiling revealed covalent interaction of EN450 with an allosteric C111 in the E2 ubiquitin-conjugating enzyme UBE2D. Quantitative proteomic profiling revealed the degradation of the oncogenic transcription factor NFKB1 as a putative degradation target. Our study thus puts forth the discovery of a covalent molecular glue degrader that uniquely induced the proximity of an E2 with a transcription factor to induce its degradation in cancer cells. Competing Interests: Declaration of interests J.A.T., J.M.K., and D.D. are employees of Novartis Institutes for BioMedical Research. This study was funded by the Novartis Institutes for BioMedical Research and the Novartis-Berkeley Translational Chemical Biology Institute. D.K.N. is a co-founder, shareholder, and on the scientific advisory boards for Frontier Medicines and Vicinitas Therapeutics; a member of the board of directors for Vicinitas Therapeutics; on the scientific advisory boards of The Mark Foundation for Cancer Research, Photys Therapeutics, Apertor Pharmaceuticals, Ecto Therapeutics, Oerth Bio, and Chordia Therapeutics; and on the investment advisory board of Droia Ventures. (Copyright © 2023 Elsevier Ltd. All rights reserved.) |
| التعليقات: | Comment in: Cell Chem Biol. 2023 Apr 20;30(4):340-342. (PMID: 37084716) |
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| معلومات مُعتمدة: | R01 CA240981 United States CA NCI NIH HHS; R35 CA263814 United States CA NCI NIH HHS; S10 OD024998 United States OD NIH HHS |
| فهرسة مساهمة: | Keywords: E2 ligase; NFKB1; UBE2D; activity-based protein profiling; molecular glue; targeted protein degradation; transcription factor |
| المشرفين على المادة: | 0 (NF-kappa B) 0 (Ligands) EC 3.4.25.1 (Proteasome Endopeptidase Complex) EC 2.3.2.27 (Ubiquitin-Protein Ligases) |
| تواريخ الأحداث: | Date Created: 20230310 Date Completed: 20230425 Latest Revision: 20240421 |
| رمز التحديث: | 20240421 |
| مُعرف محوري في PubMed: | PMC10121878 |
| DOI: | 10.1016/j.chembiol.2023.02.008 |
| PMID: | 36898369 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 2451-9448 |
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| DOI: | 10.1016/j.chembiol.2023.02.008 |