title: Switch control pocket inhibitors of p38-MAP kinase. Durable type II inhibitors that do not require binding into the canonical ATP hinge region.
abstract: Switch control pocket inhibitors of p38-alpha kinase are described. Durable type II inhibitors were designed which bind to arginines (Arg67 or Arg70) that function as key residues for mediating phospho-threonine 180 dependant conformational fluxing of p38-alpha from an inactive type II state to an active type I state. Binding to Arg70 in particular led to potent inhibitors, exemplified by DP-802, which also exhibited high kinase selectivity. Binding to Arg70 obviated the requirement for binding into the ATP Hinge region. X-ray crystallography revealed that DP-802 and analogs induce an enhanced type II conformation upon binding to either the unphosphorylated or the doubly phosphorylated form of p38-alpha kinase.
authors.affiliation: Deciphera Pharmaceuticals LLC, 643 Massachusetts St, Lawrence, KS 66044, USA.
authors.forename: Yu Mi
authors.initials: YM
authors.lastname: Ahn
authors.forename: Michael
authors.initials: M
authors.lastname: Clare
authors.forename: Carol L
authors.initials: CL
authors.lastname: Ensinger
authors.forename: Molly M
authors.initials: MM
authors.lastname: Hood
authors.forename: John W
authors.initials: JW
authors.lastname: Lord
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Lu
authors.forename: David F
authors.initials: DF
authors.lastname: Miller
authors.forename: William C
authors.initials: WC
authors.lastname: Patt
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Smith
authors.forename: Lakshminarayana
authors.initials: L
authors.lastname: Vogeti
authors.forename: Michael D
authors.initials: MD
authors.lastname: Kaufman
authors.forename: Peter A
authors.initials: PA
authors.lastname: Petillo
authors.forename: Scott C
authors.initials: SC
authors.lastname: Wise
authors.forename: Jan
authors.initials: J
authors.lastname: Abendroth
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chun
authors.forename: Robin
authors.initials: R
authors.lastname: Clark
authors.forename: Michael
authors.initials: M
authors.lastname: Feese
authors.forename: Hidong
authors.initials: H
authors.lastname: Kim
authors.forename: Lance
authors.initials: L
authors.lastname: Stewart
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Flynn
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry*; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C556098:DP 802; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D000255:Adenosine Triphosphate; D048308:Mitogen-Activated Protein Kinase 14