9FPD

Crystal structure of human TAK1/TAB1 fusion protein in complex with compound S1

This is a non-PDB format compatible entry.

Summary for 9FPD

• Entry DOI: 10.2210/pdb9fpd/pdb
• Descriptor: Mitogen-activated protein kinase kinase kinase 7,TGF-beta-activated kinase 1 and MAP3K7-binding protein 1, 6-[5-[6-(4-oxidanylcyclohexyl)oxy-1~{H}-pyrrolo[2,3-b]pyridin-5-yl]-1,2-oxazol-3-yl]pyridine-2-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 36417.71

Authors

Scheufler, C.,Lammens, A. (deposition date: 2024-06-13, release date: 2024-12-04, Last modification date: 2024-12-25)

Primary citation

Langlois, J.B.,Brenneisen, S.,Rodde, S.,Vangrevelinghe, E.,Rose, G.,Lerch, P.,Sorge, M.,Ullrich, T.,Patora-Komisarska, K.,Quancard, J.,Larger, P.,Gianola, L.,Textor, C.,Chenal, G.,Rubic-Schneider, T.,Simkova, K.,Masmanidou, O.,Scheufler, C.,Lammens, A.,Bouzan, A.,Demirci, S.,Flotte, L.,Rivet, H.,Hartmann, L.,Guezel, D.,Flueckiger, M.,Schilb, A.,Schuepbach, E.,Kettle, R.,Jacobi, C.,Pearson, D.,Richards, P.J.,Minetti, G.C.
Identification of TAK-756, A Potent TAK1 Inhibitor for the Treatment of Osteoarthritis through Intra-Articular Administration.
J.Med.Chem., 67:21163-21185, 2024

PubMed 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.

PubMed: 39576936
DOI: 10.1021/acs.jmedchem.4c01938

Experimental method

X-RAY DIFFRACTION (2.402 Å)