title: Proteome-wide drug screening using mass spectrometric imaging of bead-arrays.
abstract: A fundamental challenge in the drug discovery process is to develop compounds with high efficacy and minimal side-effects. We describe a new approach to proteome-wide drug screening for detection of on- and off-target binding which combines the advantages of mass spectrometry with microarray technology. The method involves matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI) of agarose micro-beads randomly arrayed at high-density in custom micro-well plates. Each bead carries a unique protein target and a corresponding photocleavable mass-tag for coding (PC-Mass-Tag). Compounds bound to specific protein beads and a photo-released coding PC-Mass-Tag are detected simultaneously using MALDI-MSI. As an initial demonstration of this approach, two kinase-targeted drugs, Dasatinib and Brigatinib (AP26113), were simultaneously screened against a model 50-member kinase-bead library. A MALDI-MSI scan performed at the equivalent density of 495,000 beads in the footprint of a microscope slide yielded 100% sensitivity for detecting known strong interactions with no false positives.
authors.affiliation: AmberGen, Inc., 313 Pleasant Street, Watertown, MA 02472, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: AmberGen, Inc., 313 Pleasant Street, Watertown, MA 02472, United States.
authors.forename: Ziying
authors.initials: Z
authors.lastname: Liu
authors.affiliation: AmberGen, Inc., 313 Pleasant Street, Watertown, MA 02472, United States.|Molecular Biophysics Laboratory, Department of Physics and Photonics Center, Boston University, Boston, MA 02215, United States.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Rothschild
authors.affiliation: AmberGen, Inc., 313 Pleasant Street, Watertown, MA 02472, United States.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Lim
mesh_terms: D000069439:Dasatinib / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D013058:Mass Spectrometry / Q000379:methods*; D008863:Microspheres; D009943:Organophosphorus Compounds / Q000378:metabolism; D040081:Protein Array Analysis / Q000379:methods*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D020543:Proteome / Q000032:analysis*; D011743:Pyrimidines / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D009943:Organophosphorus Compounds; D047428:Protein Kinase Inhibitors; D020543:Proteome; D011743:Pyrimidines; C000598580:brigatinib; D000069439:Dasatinib