7ZJQ
Human TEAD3 in complex with 1-Cyclopentyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
Summary for 7ZJQ
| Entry DOI | 10.2210/pdb7zjq/pdb |
| Descriptor | Transcriptional enhancer factor TEF-5, 1-cyclopentylpyrazolo[3,4-b]pyridine-5-carboxylic acid, ... (4 entities in total) |
| Functional Keywords | immunoglobulin-like fold, activator, disease mutation, dna-binding, nucleus, phosphoprotein, transcription, transcription regulation, transcription-protein binding complex |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 102176.16 |
| Authors | Musil, D.,Sousa, C.M. (deposition date: 2022-04-11, release date: 2022-07-13, Last modification date: 2024-01-31) |
| Primary citation | Heinrich, T.,Peterson, C.,Schneider, R.,Garg, S.,Schwarz, D.,Gunera, J.,Seshire, A.,Kotzner, L.,Schlesiger, S.,Musil, D.,Schilke, H.,Doerfel, B.,Diehl, P.,Bopple, P.,Lemos, A.R.,Sousa, P.M.F.,Freire, F.,Bandeiras, T.M.,Carswell, E.,Pearson, N.,Sirohi, S.,Hooker, M.,Trivier, E.,Broome, R.,Balsiger, A.,Crowden, A.,Dillon, C.,Wienke, D. Optimization of TEAD P-Site Binding Fragment Hit into In Vivo Active Lead MSC-4106 . J.Med.Chem., 65:9206-9229, 2022 Cited by PubMed Abstract: The dysregulated Hippo pathway and, consequently, hyperactivity of the transcriptional YAP/TAZ-TEAD complexes is associated with diseases such as cancer. Prevention of YAP/TAZ-TEAD triggered gene transcription is an attractive strategy for therapeutic intervention. The deeply buried and conserved lipidation pocket (P-site) of the TEAD transcription factors is druggable. The discovery and optimization of a P-site binding fragment () are described. Utilizing structure-based design, enhancement in target potency was engineered into the hit, capitalizing on the established X-ray structure of TEAD1. The efforts culminated in the optimized in vivo tool , which exhibited desirable potency, mouse pharmacokinetic properties, and in vivo efficacy. In close correlation to compound exposure, the time- and dose-dependent downregulation of a proximal biomarker could be shown. PubMed: 35763499DOI: 10.1021/acs.jmedchem.2c00403 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.095 Å) |
Structure validation
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