6XE4

BTK Fluorocyclopropyl amide inhibitor, Compound 25

6XE4 の概要

• エントリーDOI: 10.2210/pdb6xe4/pdb
• 分子名称: Tyrosine-protein kinase BTK, (1S,2S)-N-[2'-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-3'-(hydroxymethyl)-1-methyl-6-oxo[1,6-dihydro[3,4'-bipyridine]]-5-yl]-2-fluorocyclopropane-1-carboxamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: kinase, inhibitor, inflammation, drug, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34558.39

構造登録者

Kiefer, J.R.,Crawford, J.J.,Lee, W.,Eigenbrot, C.,Yu, C. (登録日: 2020-06-11, 公開日: 2020-07-22, 最終更新日: 2024-03-06)

主引用文献

Crawford, J.J.,Lee, W.,Johnson, A.R.,Delatorre, K.J.,Chen, J.,Eigenbrot, C.,Heidmann, J.,Kakiuchi-Kiyota, S.,Katewa, A.,Kiefer, J.R.,Liu, L.,Lubach, J.W.,Misner, D.,Purkey, H.,Reif, K.,Vogt, J.,Wong, H.,Yu, C.,Young, W.B.
Stereochemical Differences in Fluorocyclopropyl Amides Enable Tuning of Btk Inhibition and Off-Target Activity.
Acs Med.Chem.Lett., 11:1588-1597, 2020

PubMed Abstract: Bruton's tyrosine kinase (Btk) is thought to play a pathogenic role in chronic immune diseases such as rheumatoid arthritis and lupus. While covalent, irreversible Btk inhibitors are approved for treatment of hematologic malignancies, they are not approved for autoimmune indications. In efforts to develop additional series of reversible Btk inhibitors for chronic immune diseases, we sought to differentiate from our clinical stage inhibitor fenebrutinib using cyclopropyl amide isosteres of the 2-aminopyridyl group to occupy the flat, lipophilic H2 pocket. While drug-like properties were retained-and in some cases improved-a safety liability in the form of hERG inhibition was observed. When a fluorocyclopropyl amide was incorporated, Btk and off-target activity was found to be stereodependent and a lead compound was identified in the form of the (,)- stereoisomer.

PubMed: 32832028
DOI: 10.1021/acsmedchemlett.0c00249

実験手法

X-RAY DIFFRACTION (1.6 Å)