4RX5

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

4RX5 の概要

• エントリーDOI: 10.2210/pdb4rx5/pdb
• 分子名称: Tyrosine-protein kinase BTK, SULFATE ION, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: protein kinase, phosphotransfer catalyst, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: Q06187
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32814.64

構造登録者

Eigenbrot, C.,Yu, C. (登録日: 2014-12-08, 公開日: 2015-12-02, 最終更新日: 2023-09-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.356 Å)