X‑ray Screening of an Electrophilic Fragment Library and Application toward the Development of a Novel ERK 1/2 Covalent Inhibitor

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, 22, a covalent ATP-competitive inhibitor
with improved potency (ERK2 IC50 = 7.8 μM), was developed.