2. Academic Validation
  3. Identification of TAK-756, A Potent TAK1 Inhibitor for the Treatment of Osteoarthritis through Intra-Articular Administration

Identification of TAK-756, A Potent TAK1 Inhibitor for the Treatment of Osteoarthritis through Intra-Articular Administration

  • J Med Chem. 2024 Dec 12;67(23):21163-21185. doi: 10.1021/acs.jmedchem.4c01938.
Jean-Baptiste Langlois 1,  Silke Brenneisen 1,  Stephane Rodde 1,  Eric Vangrevelinghe 1,  Geoffroy Rose 1,  Patrick Lerch 1,  Mickael Sorge 1,  Thomas Ullrich 1,  Krystyna Patora-Komisarska 1,  Jean Quancard 1,  Patrice Larger 1,  Lucas Gianola 1,  Claudia Textor 1,  Gaelle Chenal 1,  Tina Rubic-Schneider 1,  Katerina Simkova 1,  Olga Masmanidou 1,  Clemens Scheufler 1,  Alfred Lammens 2,  Anais Bouzan 1,  Sabrina Demirci 1,  Ludivine Flotte 1,  Helene Rivet 1,  Lilian Hartmann 1,  Danyel Guezel 1,  Manuela Flueckiger 1,  Alain Schilb 1,  Edi Schuepbach 1,  Rachel Kettle 1,  Carsten Jacobi 1,  David Pearson 1,  Peter J Richards 1,  Giulia C Minetti 1
Affiliations

Affiliations

  • 1 Novartis Biomedical Research, Postfach, CH-4002 Basel, Switzerland.
  • 2 Proteros Biostructures GmbH, Bunsenstrasse 7a, D-82152 Planegg-Martinsried, Germany.
PMID: 39576936 DOI: 10.1021/acs.jmedchem.4c01938
Abstract

Osteoarthritis (OA) is a chronic and degenerative joint disease affecting more than 500 million patients worldwide with no disease-modifying treatment approved to date. Several publications report on the transforming growth factor β-activated kinase 1 (TAK1) as a potential molecular target for OA, with complementary anti-catabolic and anti-inflammatory effects. We report herein on the development of TAK1 inhibitors with physicochemical properties suitable for intra-articular injection, with the aim to achieve high drug concentration at the affected joint, while avoiding severe toxicity associated with systemic inhibition. More specifically, reducing solubility by increasing crystallinity, while maintaining moderate lipophilicity proved to be a good compromise to ensure high and sustained free drug exposures in the joint. Furthermore, structure-based design allowed for an improvement of selectivity versus interleukin-1 receptor-associated kinases 1 and 4 (IRAK1/4). Finally, TAK-756 was discovered as a potent TAK1 inhibitor with good selectivity versus IRAK1/4 as well as excellent intra-articular pharmacokinetic properties.

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