2. Academic Validation
  3. Discovery of reversible and covalent TEAD 1 selective inhibitors MSC-1254 and MSC-5046 based on one scaffold

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

  • Bioorg Med Chem Lett. 2024 Oct 5:114:129981. doi: 10.1016/j.bmcl.2024.129981.
Emma Carswell 1,  Timo Heinrich 2,  Carl Petersson 2,  Jakub Gunera 2,  Sakshi Garg 2,  Daniel Schwarz 2,  Sarah Schlesiger 2,  Frank Fischer 2,  Thomas Eichhorn 2,  Mathew Calder 3,  Geoffrey Smith 3,  Ellen MacDonald 3,  Hollie Wilson 3,  Katherine Hazel 3,  Elisabeth Trivier 4,  Rebecca Broome 4,  Alexander Balsiger 4,  Sameer Sirohi 3,  Djordje Musil 2,  Filipe Freire 5,  Heike Schilke 2,  Christian Dillon 4,  Dirk Wienke 2
Affiliations

Affiliations

  • 1 Cancer Research Horizons, Jonas Webb Building, Babraham Research Campus, Cambridge CB22 3AT, UK. Electronic address: ecarswell@exscientia.co.uk.
  • 2 Merck Healthcare KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.
  • 3 Cancer Research Horizons, Jonas Webb Building, Babraham Research Campus, Cambridge CB22 3AT, UK.
  • 4 Cancer Research Horizons, 4NW, The Francis Crick Institute, 1 Midland Rd, London NW1 1AT, UK.
  • 5 iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, Portugal.
PMID: 39369801 DOI: 10.1016/j.bmcl.2024.129981
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.

Keywords

Hippo pathway; Oncology; TEAD inhibitor; TEAD selectivity.

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