title: Structure-Guided Design of Highly Selective and Potent Covalent Inhibitors of ERK1/2.
abstract: The RAS/RAF/MEK/ERK signaling pathway has been targeted with a number of small molecule inhibitors in oncology clinical development across multiple disease indications. Importantly, cell lines with acquired resistance to B-RAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition by small molecule inhibitors. There are a number of selective, noncovalent ERK1/2 inhibitors reported along with the promiscuous hypothemycin (and related analogues) that act via a covalent mechanism of action. This article reports the identification of multiple series of highly selective covalent ERK1/2 inhibitors informed by structure-based drug design (SBDD). As a starting point for these covalent inhibitors, reported ERK1/2 inhibitors and a chemical series identified via high-throughput screening were exploited. These approaches resulted in the identification of selective covalent tool compounds for potential in vitro and in vivo studies to assess the risks and or benefits of targeting this pathway through such a mechanism of action.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Ward
authors.forename: Nicola
authors.initials: N
authors.lastname: Colclough
authors.forename: Mairi
authors.initials: M
authors.lastname: Challinor
authors.forename: Judit E
authors.initials: JE
authors.lastname: Debreczeni
authors.forename: Kay
authors.initials: K
authors.lastname: Eckersley
authors.forename: Gary
authors.initials: G
authors.lastname: Fairley
authors.forename: Lyman
authors.initials: L
authors.lastname: Feron
authors.forename: Vikki
authors.initials: V
authors.lastname: Flemington
authors.forename: Mark A
authors.initials: MA
authors.lastname: Graham
authors.forename: Ryan
authors.initials: R
authors.lastname: Greenwood
authors.forename: Philip
authors.initials: P
authors.lastname: Hopcroft
authors.forename: Tina D
authors.initials: TD
authors.lastname: Howard
authors.forename: Michael
authors.initials: M
authors.lastname: James
authors.forename: Clifford D
authors.initials: CD
authors.lastname: Jones
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Jones
authors.forename: Jonathan
authors.initials: J
authors.lastname: Renshaw
authors.forename: Karen
authors.initials: K
authors.lastname: Roberts
authors.forename: Lindsay
authors.initials: L
authors.lastname: Snow
authors.forename: Michael
authors.initials: M
authors.lastname: Tonge
authors.forename: Kay
authors.initials: K
authors.lastname: Yeung
mesh_terms: D000595:Amino Acid Sequence; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D015151:Immunoblotting; D019950:Mitogen-Activated Protein Kinase 1 / Q000737:chemistry*; D048052:Mitogen-Activated Protein Kinase 3 / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3