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Human TEAD3 in complex with 1-Cyclopentyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
Structural highlights
FunctionTEAD3_HUMAN Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Acts by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction. Binds to multiple functional elements of the human chorionic somatomammotropin-B gene enhancer.[1] [2] Publication Abstract from PubMedThe 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 (1) 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 MSC-4106, 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. Optimization of TEAD P-Site Binding Fragment Hit into In Vivo Active Lead MSC-4106.,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 AR, Sousa PMF, Freire F, Bandeiras TM, Carswell E, Pearson N, Sirohi S, Hooker M, Trivier E, Broome R, Balsiger A, Crowden A, Dillon C, Wienke D J Med Chem. 2022 Jun 28. doi: 10.1021/acs.jmedchem.2c00403. PMID:35763499[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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