Design and Development of a Series of Potent and Selective Type II Inhibitors of CDK8.
Using Sorafenib as a starting point, a series of potent and selective inhibitors of CDK8 was developed. When cocrystallized with CDK8 and cyclin C, these compounds exhibit a Type-II (DMG-out) binding mode.
Department of Discovery Chemistry, Department of Translational Oncology, Department of Structural Biology, Department of Small Molecule Biochemical Pharmacology, Department of Pathology, Department of Drug Metabolism, and Department of Protein Chemistry, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Philippe
P
Bergeron
Department of Discovery Chemistry, Department of Translational Oncology, Department of Structural Biology, Department of Small Molecule Biochemical Pharmacology, Department of Pathology, Department of Drug Metabolism, and Department of Protein Chemistry, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Michael F T
MF
Koehler
Department of Discovery Chemistry, Department of Translational Oncology, Department of Structural Biology, Department of Small Molecule Biochemical Pharmacology, Department of Pathology, Department of Drug Metabolism, and Department of Protein Chemistry, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Elizabeth M
EM
Blackwood
Department of Discovery Chemistry, Department of Translational Oncology, Department of Structural Biology, Department of Small Molecule Biochemical Pharmacology, Department of Pathology, Department of Drug Metabolism, and Department of Protein Chemistry, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Krista
K
Bowman
Department of Discovery Chemistry, Department of Translational Oncology, Department of Structural Biology, Department of Small Molecule Biochemical Pharmacology, Department of Pathology, Department of Drug Metabolism, and Department of Protein Chemistry, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Kevin
K
Clark
Department of Discovery Chemistry, Department of Translational Oncology, Department of Structural Biology, Department of Small Molecule Biochemical Pharmacology, Department of Pathology, Department of Drug Metabolism, and Department of Protein Chemistry, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Ron
R
Firestein
Department of Discovery Chemistry, Department of Translational Oncology, Department of Structural Biology, Department of Small Molecule Biochemical Pharmacology, Department of Pathology, Department of Drug Metabolism, and Department of Protein Chemistry, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
James R
JR
Kiefer
Proteros Biostructures GmbH , Bunsenstr. 7a, D-82152 Martinsried, Germany.
Klaus
K
Maskos
Department of Discovery Chemistry, Department of Translational Oncology, Department of Structural Biology, Department of Small Molecule Biochemical Pharmacology, Department of Pathology, Department of Drug Metabolism, and Department of Protein Chemistry, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Mark L
ML
McCleland
Department of Discovery Chemistry, Department of Translational Oncology, Department of Structural Biology, Department of Small Molecule Biochemical Pharmacology, Department of Pathology, Department of Drug Metabolism, and Department of Protein Chemistry, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Linda
L
Orren
Department of Discovery Chemistry, Department of Translational Oncology, Department of Structural Biology, Department of Small Molecule Biochemical Pharmacology, Department of Pathology, Department of Drug Metabolism, and Department of Protein Chemistry, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Sreemathy
S
Ramaswamy
Department of Discovery Chemistry, Department of Translational Oncology, Department of Structural Biology, Department of Small Molecule Biochemical Pharmacology, Department of Pathology, Department of Drug Metabolism, and Department of Protein Chemistry, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Laurent
L
Salphati
Department of Discovery Chemistry, Department of Translational Oncology, Department of Structural Biology, Department of Small Molecule Biochemical Pharmacology, Department of Pathology, Department of Drug Metabolism, and Department of Protein Chemistry, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Steve
S
Schmidt
Proteros Biostructures GmbH, Bunsenstr. 7a, D-82152 Martinsried, Germany; Max-Planck-Institut für Biochemie, Am Klopferspitz 18a, D-82152 Martinsried, Germany.
Elisabeth V
EV
Schneider
Department of Discovery Chemistry, Department of Translational Oncology, Department of Structural Biology, Department of Small Molecule Biochemical Pharmacology, Department of Pathology, Department of Drug Metabolism, and Department of Protein Chemistry, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Jiansheng
J
Wu
Department of Discovery Chemistry, Department of Translational Oncology, Department of Structural Biology, Department of Small Molecule Biochemical Pharmacology, Department of Pathology, Department of Drug Metabolism, and Department of Protein Chemistry, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Maureen
M
Beresini
CDK8; DMG-out; Sorafenib; inhibitor