8AO6

electrophilic inhibitor (7) of ERK2

8AO6 の概要

• エントリーDOI: 10.2210/pdb8ao6/pdb
• 分子名称: Mitogen-activated protein kinase 1, SULFATE ION, DI(HYDROXYETHYL)ETHER, ... (6 entities in total)
• 機能のキーワード: serine-threonine kinase, transcriptional repressor, cell cycle, atp binding, signaling protein
• 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: 43205.64

構造登録者

Cleasby, A. (登録日: 2022-08-08, 公開日: 2022-09-28, 最終更新日: 2024-11-06)

主引用文献

St Denis, J.D.,Chessari, G.,Cleasby, A.,Cons, B.D.,Cowan, S.,Dalton, S.E.,East, C.,Murray, C.W.,O'Reilly, M.,Peakman, T.,Rapti, M.,Stow, J.L.
X-ray Screening of an Electrophilic Fragment Library and Application toward the Development of a Novel ERK 1/2 Covalent Inhibitor.
J.Med.Chem., 65:12319-12333, 2022

PubMed Abstract: Fragment-based drug discovery (FBDD) has become an established method for the identification of efficient starting points for drug discovery programs. In recent years, electrophilic fragment screening has garnered increased attention from both academia and industry to identify novel covalent hits for tool compound or drug development against challenging drug targets. Herein, we describe the design and characterization of an acrylamide-focused electrophilic fragment library and screening campaign against extracellular signal-regulated kinase 2 (ERK2) using high-throughput protein crystallography as the primary hit-finding technology. Several fragments were found to have covalently modified the adenosine triphosphate (ATP) binding pocket Cys166 residue. From these hits, , a covalent ATP-competitive inhibitor with improved potency (ERK2 IC = 7.8 μM), was developed.

PubMed: 36101934
DOI: 10.1021/acs.jmedchem.2c01044

実験手法

X-RAY DIFFRACTION (1.811 Å)