Discovery of a subtype-selective, covalent inhibitor against palmitoylation pocket of TEAD3

Tian Lu; Yong Li; Wenchao Lu; TWGM Spitters; Xueyu Fang; Jun Wang; Simian Cai; Jing Gao; Yanting Zhou; Zhe Duan; Huan Xiong; Liping Liu; Qi Li; Hualiang Jiang; Kaixian Chen; Hu Zhou; Hua Lin; Huijin Feng; Bing Zhou; Christopher L. Antos; Cheng Luo

Acta Pharmaceutica Sinica B (Oct 2021)

Discovery of a subtype-selective, covalent inhibitor against palmitoylation pocket of TEAD3

Tian Lu,
Yong Li,
Wenchao Lu,
TWGM Spitters,
Xueyu Fang,
Jun Wang,
Simian Cai,
Jing Gao,
Yanting Zhou,
Zhe Duan,
Huan Xiong,
Liping Liu,
Qi Li,
Hualiang Jiang,
Kaixian Chen,
Hu Zhou,
Hua Lin,
Huijin Feng,
Bing Zhou,
Christopher L. Antos,
Cheng Luo

Affiliations

Tian Lu: School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Yong Li: The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
Wenchao Lu: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
TWGM Spitters: School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Xueyu Fang: School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Jun Wang: School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
Simian Cai: School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Jing Gao: Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Yanting Zhou: Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Zhe Duan: The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmacy, Nanchang University, Nanchang 330006, China
Huan Xiong: Pharmacological and Toxicological Chemistry and Biochemistry Laboratory, UMR 8601 CNRS, University of Paris, Paris Cedex 06, 75270, France
Liping Liu: The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Qi Li: The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Hualiang Jiang: The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Kaixian Chen: School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
Hu Zhou: Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Hua Lin: The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Huijin Feng: Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Bing Zhou: Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; Corresponding authors. Tel: +86 21 20685446.
Christopher L. Antos: School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Corresponding authors. Tel: +86 21 20685446.
Cheng Luo: School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; Corresponding authors. Tel: +86 21 20685446.

Journal volume & issue: Vol. 11, no. 10
pp. 3206 – 3219

Abstract

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The TEA domain (TEAD) family proteins (TEAD1‒4) are essential transcription factors that control cell differentiation and organ size in the Hippo pathway. Although the sequences and structures of TEAD family proteins are highly conserved, each TEAD isoform has unique physiological and pathological functions. Therefore, the development and discovery of subtype selective inhibitors for TEAD protein will provide important chemical probes for the TEAD-related function studies in development and diseases. Here, we identified a novel TEAD1/3 covalent inhibitor (DC-TEADin1072) with biochemical IC50 values of 0.61 ± 0.02 and 0.58 ± 0.12 μmol/L against TEAD1 and TEAD3, respectively. Further chemical optimization based on DC-TEAD in 1072 yielded a selective TEAD3 inhibitor DC-TEAD3in03 with the IC50 value of 0.16 ± 0.03 μmol/L, which shows 100-fold selectivity over other TEAD isoforms in activity-based protein profiling (ABPP) assays. In cells, DC-TEAD3in03 showed selective inhibitory effect on TEAD3 in GAL4-TEAD (1–4) reporter assays with the IC50 value of 1.15 μmol/L. When administered to zebrafish juveniles, experiments showed that DC-TEAD3in03 reduced the growth rate of zebrafish caudal fins, indicating the importance of TEAD3 activity in controlling proportional growth of vertebrate appendages.

Published in Acta Pharmaceutica Sinica B

ISSN: 2211-3835 (Print); 2211-3843 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: http://www.journals.elsevier.com/acta-pharmaceutica-sinica-b

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