2. Academic Validation
  3. Expanding the Chemical Space of Transforming Growth Factor-β (TGFβ) Receptor Type II Degraders with 3,4-Disubstituted Indole Derivatives

Expanding the Chemical Space of Transforming Growth Factor-β (TGFβ) Receptor Type II Degraders with 3,4-Disubstituted Indole Derivatives

  • ACS Pharmacol Transl Sci. 2024 Mar 21;7(4):1069-1085. doi: 10.1021/acsptsci.3c00371.
Daniel Längle 1,  Stephanie Wojtowicz-Piotrowski 2,  Till Priegann 1,  Niklas Keller 1,  Fabian Wesseler 1 3,  Elena S Reckzeh 3,  Karsten Steffens 1,  Christoph Grathwol 4,  Jana Lemke 4,  Maren Flasshoff 3,  Christian Näther 5,  Anna C Jonson 6,  Andreas Link 4,  Oliver Koch 3 7,  Gianni M Di Guglielmo 2,  Dennis Schade 1 8
Affiliations

Affiliations

  • 1 Department of Pharmaceutical & Medicinal Chemistry, Christian-Albrechts-University of Kiel, Gutenbergstrasse 76, 24118 Kiel, Germany.
  • 2 Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London N6A 5C1, ON, Canada.
  • 3 Faculty of Chemistry and Chemical Biology, Technical University Dortmund, Otto-Hahn-Strasse 6, 44227 Dortmund, Germany.
  • 4 Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Strasse 17, 17489 Greifswald, Germany.
  • 5 Institute of Inorganic Chemistry, Christian-Albrechts-University of Kiel, Max-Eyth-Straße 2, 24118 Kiel, Germany.
  • 6 Early Chemical Development, Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca Gothenburg, Mölndal SE-43183, Sweden.
  • 7 Institute of Pharmaceutical and Medicinal Chemistry and German Center of Infection Research, Münster 48149, Germany.
  • 8 Partner Site Kiel, DZHK, German Center for Cardiovascular Research, 24105 Kiel, Germany.
PMID: 38633593 DOI: 10.1021/acsptsci.3c00371
Abstract

The TGFβ type II receptor (TβRII) is a central player in all TGFβ signaling downstream events, has been linked to Cancer progression, and thus, has emerged as an auspicious anti-TGFβ strategy. Especially its targeted degradation presents an excellent goal for effective TGFβ pathway inhibition. Here, cellular structure-activity relationship (SAR) data from the TβRII degrader chemotype 1 was successfully transformed into predictive ligand-based pharmacophore models that allowed scaffold hopping. Two distinct 3,4-disubstituted indoles were identified from virtual screening: tetrahydro-4-oxo-indole 2 and indole-3-acetate 3. Design, synthesis, and screening of focused amide libraries confirmed 2r and 3n as potent TGFβ inhibitors. They were validated to fully recapitulate the ability of 1 to selectively degrade TβRII, without affecting TβRI. Consequently, 2r and 3n efficiently blocked endothelial-to-mesenchymal transition and cell migration in different Cancer cell lines while not perturbing the microtubule network. Hence, 2 and 3 present novel TβRII degrader chemotypes that will (1) aid target deconvolution efforts and (2) accelerate proof-of-concept studies for small-molecule-driven TβRII degradation in vivo.

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