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

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-132172
    98.75%, TAK1 Inhibitor