Discovery of reversible and covalent TEAD 1 selective inhibitors MSC-1254 and MSC-5046 based on one scaffold

The Transcriptional Enhanced Associated Domain (TEAD) family of transcription factors are key components of the Hippo signalling family which play a crucial role in the regulation of cell proliferation, differentiation and apoptosis. The identification of inhibitors of the TEAD transcription factors are an attractive strategy for the development of novel anticancer therapies. A HTS campaign identified hit 1, which was optimised using structure-based drug design, to deliver potent TEAD1 selective inhibitors with both a reversible and covalent mode of inhibition. The preference for TEAD1 could be rationalised by steric differences observed in the lower pocket of the palmitoylation-site between subtypes, with TEAD1 having the largest available volume to accommodate substitution in this region.

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Publication Details

Journal
Bioorganic & Medicinal Chemistry Letters
Published
2024-10-05
DOI
https://doi.org/10.1016/j.bmcl.2024.129981
Citations
5
Primary Topic
Hippo pathway signaling and YAP/TAZ
Type
article
Field-Weighted Citation Impact
1.63
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article

Discovery of reversible and covalent TEAD 1 selective inhibitors MSC-1254 and MSC-5046 based on one scaffold

Filipe Freire, Dirk Wienke, Emma L. Carswell, Christian Dillon et al.
5 citations
Bioorganic & Medicinal Chemistry Letters
Hippo pathway signaling and YAP/TAZ
1.63
article

Discovery of reversible and covalent TEAD 1 selective inhibitors MSC-1254 and MSC-5046 based on one scaffold

Filipe Freire, Dirk Wienke, Emma L. Carswell, Christian Dillon, Alexander Balsiger, Sameer Sirohi, Jakub Gunera, Mathew Calder, Timo Heinrich, Dániel Schwarz, Sarah Schlesiger, Geoffrey R. Smith, Heike Schilke, Elisabeth Trivier, Carl Petersson, Sakshi Garg, Rebecca Broome, S. Ellen Macdonald, Djordje Müsil, Frank Fischer, Thomas Eichhorn, Katherine Hazel, Hollie Wilson
article en
5 citations

Abstract

The Transcriptional Enhanced Associated Domain (TEAD) family of transcription factors are key components of the Hippo signalling family which play a crucial role in the regulation of cell proliferation, differentiation and apoptosis. The identification of inhibitors of the TEAD transcription factors are an attractive strategy for the development of novel anticancer therapies. A HTS campaign identified hit 1, which was optimised using structure-based drug design, to deliver potent TEAD1 selective inhibitors with both a reversible and covalent mode of inhibition. The preference for TEAD1 could be rationalised by steric differences observed in the lower pocket of the palmitoylation-site between subtypes, with TEAD1 having the largest available volume to accommodate substitution in this region.

Bioorganic & Medicinal Chemistry LettersVol. 114
Merck KGaA, Darmstadt (Germany) (DE), The Francis Crick Institute (GB), Cancer Research UK (GB), Babraham Bioscience Technologies (United Kingdom) (GB), Instituto de Biologia Experimental e Tecnológica (PT)
Zero hunger
Openalex Percentile: Top 18%
Hippo pathway signaling and YAP/TAZ
1.63
DOIOpen Access PDFOpenAlex
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