title: Structure-guided optimization of small molecule c-Abl activators.
abstract: c-Abl kinase is maintained in its normal inactive state in the cell through an assembled, compact conformation. We describe two chemical series that bind to the myristoyl site of the c-Abl kinase domain and stimulate c-Abl activation. We hypothesize that these molecules activate c-Abl either by blocking the C-terminal helix from adopting a bent conformation that is critical for the formation of the autoinhibited conformation or by simply providing no stabilizing interactions to the bent conformation of this helix. Structure-based molecular modeling guided the optimization of binding and activation of c-Abl of these two chemical series and led to the discovery of c-Abl activators with nanomolar potency. The small molecule c-Abl activators reported herein could be used as molecular tools to investigate the biological functions of c-Abl and therapeutic implications of its activation.
authors.affiliation: Platform Technology and Science, GlaxoSmithKline, Collegeville, PA, USA, xuan.2.hong@gsk.com.
authors.forename: Xuan
authors.initials: X
authors.lastname: Hong
authors.forename: Ping
authors.initials: P
authors.lastname: Cao
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Washio
authors.forename: Graham
authors.initials: G
authors.lastname: Simpson
authors.forename: Nino
authors.initials: N
authors.lastname: Campobasso
authors.forename: Jingsong
authors.initials: J
authors.lastname: Yang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Borthwick
authors.forename: George
authors.initials: G
authors.lastname: Burton
authors.forename: Julien
authors.initials: J
authors.lastname: Chabanet
authors.forename: Sophie
authors.initials: S
authors.lastname: Bertrand
authors.forename: Helen
authors.initials: H
authors.lastname: Evans
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Young
authors.forename: Junya
authors.initials: J
authors.lastname: Qu
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.forename: Josh
authors.initials: J
authors.lastname: Cottom
authors.forename: Paris
authors.initials: P
authors.lastname: Ward
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Thau
authors.initials: T
authors.lastname: Ho
authors.forename: Donghui
authors.initials: D
authors.lastname: Qin
authors.forename: Siegfried
authors.initials: S
authors.lastname: Christensen
authors.forename: Martha S
authors.initials: MS
authors.lastname: Head
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000737:chemistry / Q000378:metabolism*; D011720:Pyrazoles / Q000737:chemistry; D054852:Small Molecule Libraries / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D011720:Pyrazoles; D054852:Small Molecule Libraries; D016315:Proto-Oncogene Proteins c-abl