title: Development of a Potent, Specific CDK8 Kinase Inhibitor Which Phenocopies CDK8/19 Knockout Cells.
abstract: Beginning with promiscuous COT inhibitors, which were found to inhibit CDK8, a series of 6-aza-benzothiophene containing compounds were developed into potent, selective CDK8 inhibitors. When cocrystallized with CDK8 and cyclin C, these compounds exhibit an unusual binding mode, making a single hydrogen bond to the hinge residue A100, a second to K252, and a key cation-π interaction with R356. Structure-based drug design resulted in tool compounds 13 and 32, which are highly potent, kinase selective, permeable compounds with a free fraction >2% and no measurable efflux. Despite these attractive properties, these compounds exhibit weak antiproliferative activity in the HCT-116 colon cancer cell line. Further examination of the activity of 32 in this cell line revealed that the compound reduced phosphorylation of the known CDK8 substrate STAT1 in a manner identical to a CDK8 knockout clone, illustrating the complex effects of inhibition of CDK8 kinase activity in proliferation in these cells.
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, Structural Biology, Biochemical and Cellular Pharmacology, Pathology, Drug Metabolism and Pharmacokinetics, and Structural Biology, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Michael F T
authors.initials: MF
authors.lastname: Koehler
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, Structural Biology, Biochemical and Cellular Pharmacology, Pathology, Drug Metabolism and Pharmacokinetics, and Structural Biology, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bergeron
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, Structural Biology, Biochemical and Cellular Pharmacology, Pathology, Drug Metabolism and Pharmacokinetics, and Structural Biology, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Blackwood
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, Structural Biology, Biochemical and Cellular Pharmacology, Pathology, Drug Metabolism and Pharmacokinetics, and Structural Biology, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Krista
authors.initials: K
authors.lastname: Bowman
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, Structural Biology, Biochemical and Cellular Pharmacology, Pathology, Drug Metabolism and Pharmacokinetics, and Structural Biology, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Clark
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, Structural Biology, Biochemical and Cellular Pharmacology, Pathology, Drug Metabolism and Pharmacokinetics, and Structural Biology, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Ron
authors.initials: R
authors.lastname: Firestein
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, Structural Biology, Biochemical and Cellular Pharmacology, Pathology, Drug Metabolism and Pharmacokinetics, and Structural Biology, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: James R
authors.initials: JR
authors.lastname: Kiefer
authors.affiliation: Proteros Biostructures GmbH , Bunsenstr. 7a, D-82152 Martinsried, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Maskos
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, Structural Biology, Biochemical and Cellular Pharmacology, Pathology, Drug Metabolism and Pharmacokinetics, and Structural Biology, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Mark L
authors.initials: ML
authors.lastname: McCleland
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, Structural Biology, Biochemical and Cellular Pharmacology, Pathology, Drug Metabolism and Pharmacokinetics, and Structural Biology, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Linda
authors.initials: L
authors.lastname: Orren
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, Structural Biology, Biochemical and Cellular Pharmacology, Pathology, Drug Metabolism and Pharmacokinetics, and Structural Biology, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, Structural Biology, Biochemical and Cellular Pharmacology, Pathology, Drug Metabolism and Pharmacokinetics, and Structural Biology, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Proteros Biostructures GmbH, Bunsenstr. 7a, D-82152 Martinsried, Germany; Max-Planck-Institut für Biochemie, Am Klopferspitz 18a, D-82152 Martinsried, Germany.
authors.forename: Elisabeth V
authors.initials: EV
authors.lastname: Schneider
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, Structural Biology, Biochemical and Cellular Pharmacology, Pathology, Drug Metabolism and Pharmacokinetics, and Structural Biology, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Wu
authors.affiliation: Departments of Discovery Chemistry, Translational Oncology, Structural Biology, Biochemical and Cellular Pharmacology, Pathology, Drug Metabolism and Pharmacokinetics, and Structural Biology, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Maureen H
authors.initials: MH
authors.lastname: Beresini
keywords: CDK8; cyclin C; kinase inhibitor