윤호종 (Broad Institute of MIT and Harvard, 현 The University of Texas MD Anderson Cancer Center) | 한빛사논문 > 한빛사

한빛사논문

조회155

Broad Institute of MIT and Harvard, 현 The University of Texas MD Anderson Cancer Center

Nature, 05 August 2026 | https://doi.org/10.1038/s41586-026-10873-1 DCAF11-dependent molecular glue degrader activated by glutathionylation

Hojong Yoon^1,2,7,8,9, Franziska Wachter^3,4,5,9, Katharine A. Barrett¹, Cyrus Jin^4,5, Anna Rodríguez-Pöhnlein⁴, Justine C. Rutter¹, Ryan J. Lumpkin^4,5, Rebecca J. Metivier^4,5, Katherine A. Donovan^4,5, Kheewoong Baek^4,5, Yongying Jiang⁶, Minwoo Lee⁶, Robert W. Kalis¹, Jianwei Che^4,5, Yuan Xiong^4,5, Eric S. Fischer^4,5* & Benjamin L. Ebert^1,2 *

¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
²Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA, USA.
⁴Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁵Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
⁶Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁷Present address: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸Present address: James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁹These authors contributed equally: Hojong Yoon, Franziska Wachter.

^*Corresponding authors
Correspondence to Eric S. Fischer or Benjamin L. Ebert.

Abstract

Targeted protein degradation is a powerful pharmacological strategy that harnesses the ubiquitin proteasome system to eliminate disease-relevant proteins, including otherwise undruggable proteins1. Here we report an unbiased and broadly applicable platform for the systematic discovery of molecular glues across diverse E3 ligases. Using multiplexed mass spectrometry-based chemical screening, we identified M12, a molecular glue that reprogrammes the E3 ligase DCAF11 to degrade DDX18. Mechanistically, M12 functions as a prodrug that is activated through glutathione S-transferase-mediated glutathionylation. The glutathione moiety binds to an evolutionary conserved glutathione-binding site on DCAF11, and the exposed M12 moiety facilitates neo-substrate recruitment. We demonstrate that this glutathione-dependent mechanism readily enables targeted degradation of a range of proteins. Collectively, these findings establish that metabolically activated compounds can redirect E3 ligase function, thereby expanding the scope of targeted protein degradation and chemically induced proximity.

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