6DI3

CRYSTAL STRUCTURE OF BTK IN COMPLEX WITH FRAGMENT LIGAND

6DI3 の概要

• エントリーDOI: 10.2210/pdb6di3/pdb
• 関連するPDBエントリー: 6di0
• 分子名称: Tyrosine-protein kinase BTK, 6-[(3S)-3-(acryloylamino)pyrrolidin-1-yl]-2-(4-phenoxyphenoxy)pyridine-3-carboxamide (3 entities in total)
• 機能のキーワード: lead optimization, fragment screening by x-ray, 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: 32042.77

構造登録者

GARDBERG, A. (登録日: 2018-05-22, 公開日: 2018-09-05, 最終更新日: 2024-03-13)

主引用文献

Qiu, H.,Liu-Bujalski, L.,Caldwell, R.D.,Follis, A.V.,Gardberg, A.,Goutopoulos, A.,Grenningloh, R.,Head, J.,Johnson, T.,Jones, R.,Mochalkin, I.,Morandi, F.,Neagu, C.,Sherer, B.
Discovery of potent, highly selective covalent irreversible BTK inhibitors from a fragment hit.
Bioorg. Med. Chem. Lett., 28:2939-2944, 2018

PubMed Abstract: Bruton's Tyrosine Kinase (BTK) is a member of the TEC kinase family that is expressed in cells of hematopoietic lineage (e.g., in B cells, macrophages, monocytes, and mast cells). Small molecule covalent irreversible BTK inhibitor targeting Cys481 within the ATP-binding pocket, for example ibrutinib, has been applied in the treatment of B-cell malignancies. Starting from a fragment hit, we discovered a novel series of potent covalent irreversible BTK inhibitors that occupy selectivity pocket of the active site of the BTK kinase domain. Guided by X-ray structures and a fragment-based drug design (FBDD) approach, we generated molecules showing comparable cellular potency to ibrutinib and higher kinome selectivity against undesirable off-targets like EGFR.

PubMed: 30122225
DOI: 10.1016/j.bmcl.2018.07.008

実験手法

X-RAY DIFFRACTION (2 Å)