title: Boron-based inhibitors of acyl protein thioesterases 1 and 2.
abstract: Ras proteins are of importance in cell proliferation, and hence their mutated forms play causative roles in many kinds of cancer in different tissues. Inhibition of the Ras-depalmitoylating enzyme acyl protein thioesterases APT1 and -2 is a new approach to modulating the Ras cycle. Here we present boronic and borinic acid derivatives as a new class of potent and nontoxic APT inhibitors. These compounds were detected by extensive library screening using chemical arrays and turned out to inhibit human APT1 and -2 in a competitive mode. Furthermore, one of the molecules was demonstrated to inhibit Erk1/2 phosphorylation significantly.
authors.affiliation: Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
authors.forename: Tobias J
authors.initials: TJ
authors.lastname: Zimmermann
authors.forename: Marco
authors.initials: M
authors.lastname: Bürger
authors.forename: Etsu
authors.initials: E
authors.lastname: Tashiro
authors.forename: Yasumitsu
authors.initials: Y
authors.lastname: Kondoh
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Martinez
authors.forename: Kristina
authors.initials: K
authors.lastname: Görmer
authors.forename: Sigrid
authors.initials: S
authors.lastname: Rosin-Steiner
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimizu
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Ozaki
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
authors.forename: Nobumoto
authors.initials: N
authors.lastname: Watanabe
authors.forename: Dennis
authors.initials: D
authors.lastname: Hall
authors.forename: Ingrid R
authors.initials: IR
authors.lastname: Vetter
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
authors.forename: Christian
authors.initials: C
authors.lastname: Hedberg
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
mesh_terms: D000818:Animals; D001895:Boron / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D054878:Lipoylation / Q000187:drug effects; D061985:Madin Darby Canine Kidney Cells; D013869:Thiolester Hydrolases / Q000037:antagonists & inhibitors*; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C402226:LYPLA1 protein, human; D013869:Thiolester Hydrolases; D018631:ras Proteins; D001895:Boron