title: Discovery and characterization of a cell-permeable, small-molecule c-Abl kinase activator that binds to the myristoyl binding site.
abstract: c-Abl kinase activity is regulated by a unique mechanism involving the formation of an autoinhibited conformation in which the N-terminal myristoyl group binds intramolecularly to the myristoyl binding site on the kinase domain and induces the bending of the αI helix that creates a docking surface for the SH2 domain. Here, we report a small-molecule c-Abl activator, DPH, that displays potent enzymatic and cellular activity in stimulating c-Abl activation. Structural analyses indicate that DPH binds to the myristoyl binding site and prevents the formation of the bent conformation of the αI helix through steric hindrance, a mode of action distinct from the previously identified allosteric c-Abl inhibitor, GNF-2, that also binds to the myristoyl binding site. DPH represents the first cell-permeable, small-molecule tool compound for c-Abl activation.
authors.affiliation: Oncology Research and Development, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA. jingsong.2.yang@gsk.com
authors.forename: Jingsong
authors.initials: J
authors.lastname: Yang
authors.forename: Nino
authors.initials: N
authors.lastname: Campobasso
authors.forename: Mangatt P
authors.initials: MP
authors.lastname: Biju
authors.forename: Kelly
authors.initials: K
authors.lastname: Fisher
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Pan
authors.forename: Josh
authors.initials: J
authors.lastname: Cottom
authors.forename: Sarah
authors.initials: S
authors.lastname: Galbraith
authors.forename: Thau
authors.initials: T
authors.lastname: Ho
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Xuan
authors.initials: X
authors.lastname: Hong
authors.forename: Paris
authors.initials: P
authors.lastname: Ward
authors.forename: Glenn
authors.initials: G
authors.lastname: Hofmann
authors.forename: Brett
authors.initials: B
authors.lastname: Siegfried
authors.forename: Francesca
authors.initials: F
authors.lastname: Zappacosta
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Washio
authors.forename: Ping
authors.initials: P
authors.lastname: Cao
authors.forename: Junya
authors.initials: J
authors.lastname: Qu
authors.forename: Sophie
authors.initials: S
authors.lastname: Bertrand
authors.forename: Da-Yuan
authors.initials: DY
authors.lastname: Wang
authors.forename: Martha S
authors.initials: MS
authors.lastname: Head
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.forename: Sheri
authors.initials: S
authors.lastname: Moores
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Lai
authors.forename: Kyung
authors.initials: K
authors.lastname: Johanson
authors.forename: George
authors.initials: G
authors.lastname: Burton
authors.forename: Connie
authors.initials: C
authors.lastname: Erickson-Miller
authors.forename: Graham
authors.initials: G
authors.lastname: Simpson
authors.forename: Peter
authors.initials: P
authors.lastname: Tummino
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.forename: Allen
authors.initials: A
authors.lastname: Oliff
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D006827:Hydantoins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010539:Permeability; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000737:chemistry / Q000378:metabolism*; D050737:Proto-Oncogene Proteins c-crk / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: C558635:5-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)-2,4-imidazolidinedione; D006827:Hydantoins; D050737:Proto-Oncogene Proteins c-crk; D011720:Pyrazoles; D016315:Proto-Oncogene Proteins c-abl