title: High-throughput kinase profiling: a more efficient approach toward the discovery of new kinase inhibitors.
abstract: Selective protein kinase inhibitors have only been developed against a small number of kinase targets. Here we demonstrate that "high-throughput kinase profiling" is an efficient method for the discovery of lead compounds for established as well as unexplored kinase targets. We screened a library of 118 compounds constituting two distinct scaffolds (furan-thiazolidinediones and pyrimido-diazepines) against a panel of 353 kinases. A distinct kinase selectivity profile was observed for each scaffold. Selective inhibitors were identified with submicromolar cellular activity against PIM1, ERK5, ACK1, MPS1, PLK1-3, and Aurora A,B kinases. In addition, we identified potent inhibitors for so far unexplored kinases such as DRAK1, HIPK2, and DCAMKL1 that await further evaluation. This inhibitor-centric approach permits comprehensive assessment of a scaffold of interest and represents an efficient and general strategy for identifying new selective kinase inhibitors.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Chandrasekhar V
authors.initials: CV
authors.lastname: Miduturu
authors.forename: Xianming
authors.initials: X
authors.lastname: Deng
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kwiatkowski
authors.forename: Wannian
authors.initials: W
authors.lastname: Yang
authors.forename: Laurent
authors.initials: L
authors.lastname: Brault
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.forename: Eunah
authors.initials: E
authors.lastname: Chung
authors.forename: Qingkai
authors.initials: Q
authors.lastname: Yang
authors.forename: Juerg
authors.initials: J
authors.lastname: Schwaller
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.forename: Randall W
authors.initials: RW
authors.lastname: King
authors.forename: Jiing-Dwan
authors.initials: JD
authors.lastname: Lee
authors.forename: Sanna
authors.initials: S
authors.lastname: Herrgard
authors.forename: Patrick
authors.initials: P
authors.lastname: Zarrinkar
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D064127:Aurora Kinases; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005663:Furans / Q000737:chemistry / Q000494:pharmacology; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology
chemical_list: D005663:Furans; D047428:Protein Kinase Inhibitors; D045162:Thiazolidinediones; D001569:Benzodiazepines; C089946:2,4-thiazolidinedione; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; C403262:TNK2 protein, human; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim; D048054:Mitogen-Activated Protein Kinase 7