7ZJP

Optimization of TEAD P-Site Binding Fragment Hit into In Vivo Active Lead MSC-4106

Summary for 7ZJP

• Entry DOI: 10.2210/pdb7zjp/pdb
• Descriptor: Transcriptional enhancer factor TEF-1, 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indole-7-carboxylic acid, SULFATE ION, ... (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)
• Total number of polymer chains: 2
• Total formula weight: 51928.74

Authors

Freire, F.,Heinrich, T.,Petersson, C.,Schneider, R.,Garg, S.,Schwarz, D.,Gunera, J.,Seshire, A.,Koetzner, L.,Schlesiger, S.,Musil, D.,Schilke, H.,Doerfel, B.,Diehl, P.,Boepple, 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. (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

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: 35763499
DOI: 10.1021/acs.jmedchem.2c00403

Experimental method

X-RAY DIFFRACTION (2.19 Å)