4RX5

Bruton's tyrosine kinase (BTK) with pyridazinone compound 23

Summary for 4RX5

• Entry DOI: 10.2210/pdb4rx5/pdb
• Descriptor: Tyrosine-protein kinase BTK, SULFATE ION, GLYCEROL, ... (6 entities in total)
• Functional Keywords: protein kinase, phosphotransfer catalyst, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: Q06187
• Total number of polymer chains: 1
• Total formula weight: 32814.64

Authors

Eigenbrot, C.,Yu, C. (deposition date: 2014-12-08, release date: 2015-12-02, Last modification date: 2023-09-20)

Primary citation

Young, W.B.,Barbosa, J.,Blomgren, P.,Bremer, M.C.,Crawford, J.J.,Dambach, D.,Eigenbrot, C.,Gallion, S.,Johnson, A.R.,Kropf, J.E.,Lee, S.H.,Liu, L.,Lubach, J.W.,Macaluso, J.,Maciejewski, P.,Mitchell, S.A.,Ortwine, D.F.,Di Paolo, J.,Reif, K.,Scheerens, H.,Schmitt, A.,Wang, X.,Wong, H.,Xiong, J.M.,Xu, J.,Yu, C.,Zhao, Z.,Currie, K.S.
Discovery of highly potent and selective Bruton's tyrosine kinase inhibitors: Pyridazinone analogs with improved metabolic stability.
Bioorg.Med.Chem.Lett., 26:575-579, 2016

PubMed Abstract: BTK inhibitor GDC-0834 (1) was found to be rapidly metabolized in human studies, resulting in a suspension of clinical trials. The primary route of metabolism was through cleavage of the acyclic amide bond connecting the terminal tetrahydrobenzothiophene with the central linker aryl ring. SAR studies were focused on reducing metabolic cleavage of this amide, and resulted in the identification of several central aryl linker substituents that conferred improved stability. The most promising substituted aryl linkers were then incorporated into an optimized pyridazinone scaffold, resulting in the identification of lead analog 23, possessing improved potency, metabolic stability and preclinical properties.

PubMed: 26675441
DOI: 10.1016/j.bmcl.2015.11.076

Experimental method

X-RAY DIFFRACTION (1.356 Å)