title: A novel CDK7 inhibitor of the Pyrazolotriazine class exerts broad-spectrum antiviral activity at nanomolar concentrations.
abstract: Protein kinases represent central and multifunctional regulators of a balanced virus-host interaction. Cyclin-dependent protein kinase 7 (CDK7) plays crucial regulatory roles in cell cycle and transcription, both connected with the replication of many viruses. Previously, we developed a CDK7 inhibitor, LDC4297, that inhibits CDK7 in vitro in the nano-picomolar range. Novel data from a kinome-wide evaluation (>330 kinases profiled in vitro) demonstrate a kinase selectivity. Importantly, we provide first evidence for the antiviral potential of the CDK7 inhibitor LDC4297, i.e., in exerting a block of the replication of human cytomegalovirus (HCMV) in primary human fibroblasts at nanomolar concentrations (50% effective concentration, 24.5 ± 1.3 nM). As a unique feature compared to approved antiherpesviral drugs, inhibition occurred already at the immediate-early level of HCMV gene expression. The mode of antiviral action was considered multifaceted since CDK7-regulated cellular factors that are supportive of HCMV replication were substantially affected by the inhibitors. An effect of LDC4297 was identified in the interference with HCMV-driven inactivation of retinoblastoma protein (Rb), a regulatory step generally considered a hallmark of herpesviral replication. In line with this finding, a broad inhibitory activity of the drug could be demonstrated against a selection of human and animal herpesviruses and adenoviruses, whereas other viruses only showed intermediate drug sensitivity. Summarized, the CDK7 inhibitor LDC4297 is a promising candidate for further antiviral drug development, possibly offering new options for a comprehensive approach to antiviral therapy.
authors.affiliation: Institute for Clinical and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Corina
authors.initials: C
authors.lastname: Hutterer
authors.affiliation: Lead Discovery Center GmbH, Dortmund, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Eickhoff
authors.affiliation: Institute for Clinical and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Milbradt
authors.affiliation: Institute for Clinical and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Korn
authors.affiliation: Institute for Clinical and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Zeitträger
authors.affiliation: Institute for Clinical and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Hanife
authors.initials: H
authors.lastname: Bahsi
authors.affiliation: Institute for Clinical and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Wagner
authors.affiliation: Lead Discovery Center GmbH, Dortmund, Germany.
authors.forename: Gunther
authors.initials: G
authors.lastname: Zischinsky
authors.affiliation: Lead Discovery Center GmbH, Dortmund, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Wolf
authors.affiliation: Lead Discovery Center GmbH, Dortmund, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Degenhart
authors.affiliation: Lead Discovery Center GmbH, Dortmund, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Unger
authors.affiliation: Lead Discovery Center GmbH, Dortmund, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Baumann
authors.affiliation: Lead Discovery Center GmbH, Dortmund, Germany.
authors.forename: Bert
authors.initials: B
authors.lastname: Klebl
authors.affiliation: Institute for Clinical and Molecular Virology, University of Erlangen-Nuremberg, Erlangen, Germany manfred.marschall@viro.med.uni-erlangen.de.
authors.forename: Manfred
authors.initials: M
authors.lastname: Marschall
mesh_terms: D000256:Adenoviridae / Q000187:drug effects; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D003587:Cytomegalovirus / Q000187:drug effects; D005347:Fibroblasts / Q000821:virology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D006564:Herpesviridae / Q000187:drug effects; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D018844:Cyclin-Dependent Kinases; D011720:Pyrazoles; D014227:Triazines; C000592926:LDC4297; C090586:Cdk7 protein, mouse