Discovery of a subtype-selective,covalent inhibitor against palmitoylation pocket of TEAD3 |
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| Authors: | 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 |
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| Affiliation: | 1. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China;2. 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;3. Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;4. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA;5. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China;6. School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China;7. Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;8. School of Pharmacy, Nanchang University, Nanchang 330006, China;9. Pharmacological and Toxicological Chemistry and Biochemistry Laboratory, UMR 8601 CNRS, University of Paris, Paris Cedex 06, 75270, France;10. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China |
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| Abstract: | 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. |
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| Keywords: | Hippo pathway TEAD3 Covalent inhibitor Palmitoylation inhibitor. TEAD},{#name:keyword,$:{id:kwrd0035},$$:[{#name:text,_:TEA domain family TEAD3},{#name:keyword,$:{id:kwrd0045},$$:[{#name:text,_:TEA domain transcription factor 3 YAP},{#name:keyword,$:{id:kwrd0055},$$:[{#name:text,_:Yes-associated protein TAZ},{#name:keyword,$:{id:kwrd0065},$$:[{#name:text,_:transcriptional co-activator with PDZ-binding motif ABPP},{#name:keyword,$:{id:kwrd0075},$$:[{#name:text,_:activity-based protein profiling MS},{#name:keyword,$:{id:kwrd0085},$$:[{#name:text,_:mass spectrometry HCC},{#name:keyword,$:{id:kwrd0095},$$:[{#name:text,_:hepatocellular carcinoma. |
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