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Discovery of 2,4-1H-Imidazole Carboxamides as Potent and Selective TAK1 Inhibitors.
Veerman, Johan J N; Bruseker, Yorik B; Damen, Eddy; Heijne, Erik H; van Bruggen, Wendy; Hekking, Koen F W; Winkel, Rob; Hupp, Christopher D; Keefe, Anthony D; Liu, Julie; Thomson, Heather A; Zhang, Ying; Cuozzo, John W; McRiner, Andrew J; Mulvihill, Mark J; van Rijnsbergen, Peter; Zech, Birgit; Renzetti, Louis M; Babiss, Lee; Müller, Gerhard.
Afiliación
  • Veerman JJN; ZoBio BV, J.H. Oortweg 19, 2333 CH Leiden, The Netherlands.
  • Bruseker YB; Mercachem BV, Department of Medicinal Chemistry, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands.
  • Damen E; Mercachem BV, Department of Medicinal Chemistry, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands.
  • Heijne EH; Mercachem BV, Department of Medicinal Chemistry, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands.
  • van Bruggen W; Mercachem BV, Department of Medicinal Chemistry, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands.
  • Hekking KFW; Mercachem BV, Department of Medicinal Chemistry, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands.
  • Winkel R; Mercachem BV, Department of Medicinal Chemistry, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands.
  • Hupp CD; X-Chem, Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States.
  • Keefe AD; X-Chem, Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States.
  • Liu J; Civetta Therapeutics, 10 Wilson Road, Cambridge, Massachusetts 02138, United States.
  • Thomson HA; X-Chem, Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States.
  • Zhang Y; X-Chem, Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States.
  • Cuozzo JW; X-Chem, Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States.
  • McRiner AJ; X-Chem, Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States.
  • Mulvihill MJ; HiberCell Inc., New York, New York 10019, United States.
  • van Rijnsbergen P; Mercachem BV, Department of Medicinal Chemistry, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands.
  • Zech B; AnavoTherapeutics BV, J.H. Oortweg 19, 2333 CH Leiden, The Netherlands.
  • Renzetti LM; Bridge Medicines LLC, New York, New York 10017, United States.
  • Babiss L; Wilmington, North Carolina 28405, United States.
  • Müller G; AnavoTherapeutics BV, J.H. Oortweg 19, 2333 CH Leiden, The Netherlands.
ACS Med Chem Lett ; 12(4): 555-562, 2021 Apr 08.
Article en En | MEDLINE | ID: mdl-33859795
Herein we report the discovery of 2,4-1H-imidazole carboxamides as novel, biochemically potent, and kinome selective inhibitors of transforming growth factor ß-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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: ACS Med Chem Lett Año: 2021 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: ACS Med Chem Lett Año: 2021 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Estados Unidos