PUBLICATION
Discovery of a subtype-selective, covalent inhibitor against palmitoylation pocket of TEAD3
- Authors
- Lu, T., Li, Y., Lu, W., Spitters, T., Fang, X., Wang, J., Cai, S., Gao, J., Zhou, Y., Duan, Z., Xiong, H., Liu, L., Li, Q., Jiang, H., Chen, K., Zhou, H., Lin, H., Feng, H., Zhou, B., Antos, C.L., Luo, C.
- ID
- ZDB-PUB-211104-6
- Date
- 2021
- Source
- Acta pharmaceutica Sinica. B 11: 3206-3219 (Journal)
- Registered Authors
- Antos, Christopher
- Keywords
- ABPP, activity-based protein profiling, Covalent inhibitor, HCC, hepatocellular carcinoma., Hippo pathway, MS, mass spectrometry, Palmitoylation inhibitor., TAZ, transcriptional co-activator with PDZ-binding motif, TEAD, TEA domain family, TEAD3, TEAD3, TEA domain transcription factor 3, YAP, Yes-associated protein
- MeSH Terms
- none
- PubMed
- 34729310 Full text @ Acta Pharm Sin B
Citation
Lu, T., Li, Y., Lu, W., Spitters, T., Fang, X., Wang, J., Cai, S., Gao, J., Zhou, Y., Duan, Z., Xiong, H., Liu, L., Li, Q., Jiang, H., Chen, K., Zhou, H., Lin, H., Feng, H., Zhou, B., Antos, C.L., Luo, C. (2021) Discovery of a subtype-selective, covalent inhibitor against palmitoylation pocket of TEAD3. Acta pharmaceutica Sinica. B. 11:3206-3219.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping