title: N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine.
abstract: Cyclin-dependent kinases (CDKs) and their regulators show frequent abnormalities in tumors. Ten low molecular weight pharmacologic inhibitors of CDKs are currently in clinical trials against various cancers, including the 2,6,9-trisubstituted purine (R)-roscovitine (CYC202/Seliciclib). We here report the characterization of N-&-N1, a bioisoster of roscovitine displaying improved antitumoral properties. N-&-N1 shows exquisite selectivity for CDKs, with 2- to 3-fold enhanced potency compared with (R)-roscovitine. Inhibition of retinoblastoma protein phosphorylation and RNA polymerase II Ser2 phosphorylation in neuroblastoma SH-SY5Y cells exposed to N-&-N1 indicates that N-&-N1 is able to inhibit CDKs in a cellular context. N-&-N1 also down-regulates the expression of RNA polymerase. Cocrystal structures of N-&-N1 and (R)-roscovitine in complex with CDK2/cyclin A reveal that both inhibitors adopt similar binding modes. A competitive assay shows that, compared with (R)-roscovitine, N-&-N1 has reduced affinity for Erk2 and pyridoxal kinase. N-&-N1 triggers cell death in a panel of diverse cell lines. Cell death is accompanied by events characteristic of apoptosis: cytochrome c release, activation of effector caspases, and poly(ADP-ribose) polymerase cleavage. Induction of p53 and p21CIP1 and down-regulation of the Mcl-1 antiapoptotic factor were also observed. Studies in mice show that N-&-N1 has pharmacokinetics properties similar to those of (R)-roscovitine. Altogether, these results show that analogues of (R)-roscovitine can be designed with improved antitumor potential.
authors.affiliation: Centre National de la Recherche Scientifique, Protein Phosphorylation and Human Disease Group, UPS2682, Station Biologique, B.P. 74, 29682 Roscoff cedex, Bretagne, France.
authors.forename: Karima
authors.initials: K
authors.lastname: Bettayeb
authors.forename: Hatem
authors.initials: H
authors.lastname: Sallam
authors.forename: Yoan
authors.initials: Y
authors.lastname: Ferandin
authors.forename: Florence
authors.initials: F
authors.lastname: Popowycz
authors.forename: Guy
authors.initials: G
authors.lastname: Fournet
authors.forename: Moustapha
authors.initials: M
authors.lastname: Hassan
authors.forename: Aude
authors.initials: A
authors.lastname: Echalier
authors.forename: Philippe
authors.initials: P
authors.lastname: Bernard
authors.forename: Jane
authors.initials: J
authors.lastname: Endicott
authors.forename: Benoît
authors.initials: B
authors.lastname: Joseph
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D019925:Cyclin A / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011687:Purines / Q000737:chemistry / Q000494:pharmacology*; D000077546:Roscovitine; D013552:Swine; D014020:Tissue Extracts / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D019925:Cyclin A; C532360:N&N1 compound; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011687:Purines; D014020:Tissue Extracts; D000077546:Roscovitine; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2