title: New potent dual inhibitors of CK2 and Pim kinases: discovery and structural insights.
abstract: Protein kinase casein kinase 2 (CK2) is a serine/threonine kinase with evidence of implication in growth dysregulation and apoptosis resistance, making it a relevant target for cancer therapy. Several CK2 inhibitors have been developed showing variable efficiency, emphasizing the need to expand the chemical diversity of those inhibitors. We report the identification and characterization of 2,8-difurandicarboxylic acid derivatives as a new class of nanomolar ATP-competitive inhibitors. Selectivity profiling pointed out proviral insertion Moloney virus kinases (Pim kinases) as the only other kinases that are significantly inhibited. By combining structure-activity relationship analysis with structural determination, we were able to determine the binding mode of these inhibitors for both kinases and to explain their strong inhibitory potency. Essential chemical features necessary for activity on both kinases were then identified. The described compounds are not cell permeable: however, they could provide a lead for developing novel inhibitors usable also in vivo. Given the similar but not redundant pathophysiological functions of CK2 and Pim family members, such inhibitors would provide new attractive leads for targeted cancer therapy. This work highlights that 2 functionally related kinases from different kinome branches display exquisite sensitivity to a common inhibitor.
authors.affiliation: Centre de Recherche, Institut Curie, Paris, France.
authors.forename: Miriam
authors.initials: M
authors.lastname: López-Ramos
authors.forename: Renaud
authors.initials: R
authors.lastname: Prudent
authors.forename: Virginie
authors.initials: V
authors.lastname: Moucadel
authors.forename: Céline F
authors.initials: CF
authors.lastname: Sautel
authors.forename: Caroline
authors.initials: C
authors.lastname: Barette
authors.forename: Laurence
authors.initials: L
authors.lastname: Lafanechère
authors.forename: Liliane
authors.initials: L
authors.lastname: Mouawad
authors.forename: David
authors.initials: D
authors.lastname: Grierson
authors.forename: Frédéric
authors.initials: F
authors.lastname: Schmidt
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Florent
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.forename: Alex N
authors.initials: AN
authors.lastname: Bullock
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Reiser
authors.forename: Claude
authors.initials: C
authors.lastname: Cochet
mesh_terms: D000818:Animals; D001665:Binding Sites; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000737:chemistry; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004795:Enzyme Stability; D006801:Humans; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D047390:Casein Kinase II; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim