Discovery of 2,4-1 H-Imidazole Carboxamides as Potent and Selective TAK1 Inhibitors

  • ACS Med Chem Lett. 2021 Mar 3;12(4):555-562. doi: 10.1021/acsmedchemlett.0c00547.
Johan J N Veerman  1 ,  Yorik B Bruseker  2 ,  Eddy Damen  2 ,  Erik H Heijne  2 ,  Wendy van Bruggen  2 ,  Koen F W Hekking  2 ,  Rob Winkel  2 ,  Christopher D Hupp  3 ,  Anthony D Keefe  3 ,  Julie Liu  4 ,  Heather A Thomson  3 ,  Ying Zhang  3 ,  John W Cuozzo  3 ,  Andrew J McRiner  3 ,  Mark J Mulvihill  5 ,  Peter van Rijnsbergen  2 ,  Birgit Zech  6 ,  Louis M Renzetti  7 ,  Lee Babiss  8 ,  Gerhard Müller  6
Affiliations
  • 1. ZoBio BV, J.H. Oortweg 19, 2333 CH Leiden, The Netherlands.
  • 2. Mercachem BV, Department of Medicinal Chemistry, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands.
  • 3. X-Chem, Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States.
  • 4. Civetta Therapeutics, 10 Wilson Road, Cambridge, Massachusetts 02138, United States.
  • 5. HiberCell Inc., New York, New York 10019, United States.
  • 6. AnavoTherapeutics BV, J.H. Oortweg 19, 2333 CH Leiden, The Netherlands.
  • 7. Bridge Medicines LLC, New York, New York 10017, United States.
  • 8. Wilmington, North Carolina 28405, United States.
PMID: 33859795 DOI: 10.1021/acsmedchemlett.0c00547
Abstract

Herein we report the discovery of 2,4-1H-imidazole carboxamides as novel, biochemically potent, and kinome selective inhibitors of transforming growth factor β-activated kinase 1 (TAK1). The target was subjected to a DNA-encoded chemical library (DECL) screen. After hit analysis a cluster of compounds was identified, which was based on a central pyrrole-2,4-1H-dicarboxamide scaffold, showing remarkable kinome selectivity. A scaffold-hop to the corresponding imidazole resulted in increased biochemical potency. Next, X-ray crystallography revealed a distinct binding mode compared to Other TAK1 inhibitors. A benzylamide was found in a perpendicular orientation with respect to the core hinge-binding imidazole. Additionally, an unusual amide flip was observed in the kinase hinge region. Using structure-based drug design (SBDD), key substitutions at the pyrrolidine amide and the glycine resulted in a significant increase in biochemical potency.

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