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

  • J Med Chem. 2022 Jul 14;65(13):9206-9229. doi: 10.1021/acs.jmedchem.2c00403.
Timo Heinrich  1 ,  Carl Peterson  1 ,  Richard Schneider  1 ,  Sakshi Garg  1 ,  Daniel Schwarz  1 ,  Jakub Gunera  1 ,  Anita Seshire  1 ,  Lisa Kötzner  1 ,  Sarah Schlesiger  1 ,  Djordje Musil  1 ,  Heike Schilke  1 ,  Benjamin Doerfel  1 ,  Patrizia Diehl  1 ,  Pia Böpple  1 ,  Ana R Lemos  2 ,  Pedro M F Sousa  2 ,  Filipe Freire  2 ,  Tiago M Bandeiras  2 ,  Emma Carswell  3 ,  Nicholas Pearson  3 ,  Sameer Sirohi  3 ,  Mollie Hooker  3  4 ,  Elisabeth Trivier  5 ,  Rebecca Broome  5 ,  Alexander Balsiger  5 ,  Abigail Crowden  5 ,  Christian Dillon  5 ,  Dirk Wienke  1
Affiliations
  • 1. Merck Healthcare KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.
  • 2. iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, Oeiras 2781-901, Portugal.
  • 3. Cancer Research Horizons, Jonas Webb Building, Babraham Research Campus, Cambridge CB22 3AT, U.K.
  • 4. MSD, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, U.K.
  • 5. Cancer Research Horizons, 4NW, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, U.K.
PMID: 35763499 DOI: 10.1021/acs.jmedchem.2c00403
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 (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.

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