8AO5

Specific covalent inhibitor (6) of ERK2

Summary for 8AO5

• Entry DOI: 10.2210/pdb8ao5/pdb
• Descriptor: Mitogen-activated protein kinase 1, SULFATE ION, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (5 entities in total)
• Functional Keywords: serine-threonine kinase, transcriptional repressor, cell cycle, atp binding, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 43221.65

Authors

Cleasby, A. (deposition date: 2022-08-08, release date: 2022-09-28, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.595 Å)