The First-In-Class Deubiquitinase-Targeting Chimera Stabilizes and Activates cGAS

Zhijie Deng; Li Chen; Chao Qian; Jing Liu; Qiong Wu; Xiangyang Song; Yan Xiong; Zhen Wang; Xiaoping Hu; Hiroyuki Inuzuka; Yue Zhong; Yufei Xiang; Yindan Lin; Ngoc Dung Pham; Yi Shi; Wenyi Wei; Jian Jin

doi:10.1002/anie.202415168

The First-In-Class Deubiquitinase-Targeting Chimera Stabilizes and Activates cGAS

Angew Chem Int Ed Engl. 2024 Aug 16:e202415168. doi: 10.1002/anie.202415168. Online ahead of print.

Authors

Zhijie Deng^{1

2

3}, Li Chen^{4

5}, Chao Qian^{1

2

3}, Jing Liu^{4

5}, Qiong Wu^{1

2

3}, Xiangyang Song^{1

2

3}, Yan Xiong^{1

2

3}, Zhen Wang^{4

5}, Xiaoping Hu^{1

2

3}, Hiroyuki Inuzuka^{4

5}, Yue Zhong^{1

2

3}, Yufei Xiang², Yindan Lin^{1

2

3}, Ngoc Dung Pham², Yi Shi², Wenyi Wei^{4

4

5}, Jian Jin^{6

1

2

3}

Affiliations

¹ Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, 10029, New York, New York, United States.
² Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, 10029, New York, New York, United States.
³ Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 10029, New York, New York, United States.
⁴ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 02215, Boston, Massachusetts, United States.
⁵ Present address: Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, China.
⁶ Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 10029, New York, New York, United States.

PMID: 39150898
DOI: 10.1002/anie.202415168

Abstract

Deubiquitinase-targeting chimera (DUBTAC) is a promising technology for inducing targeted protein stabilization (TPS). Despite its therapeutic potential, very few proteins have been stabilized by DUBTACs to date. The limited applicability of this technology is likely due to the modest DUBTAC-induced protein stabilization effect, and the scarcity of effective deubiquitinase ligands that can be harnessed for DUBTAC development. Here, we report the discovery of MS7829 and MS8588, the first-in-class DUBTACs of cGAS, a key component of the cGAS-STING pathway. While these DUBTACs are based on a cGAS inhibitor, they effectively stabilized cGAS and activated the cGAS/STING/IRF3 signaling. To develop these cGAS DUBTACs, we optimized EN523, an OTUB1 covalent ligand, into an improved ligand, MS5105. We validated MS5105 by generating a MS5105-based CFTR DUBTAC, which was approximately 10-fold more effective in stabilizing the ΔF508-CFTR mutant protein than the previously reported EN523-based CFTR DUBTAC. Overall, this work advances the DUBTAC technology for TPS.

Keywords: DUBTAC; OTUB1; cGAS; targeted protein stabilization; tumor suppressor.

Abstract

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