N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine

• Published in: Molecular cancer therapeutics Vol. 7; no. 9; pp. 2713 - 2724
• Main Authors: Bettayeb, Karima, Sallam, Hatem, Ferandin, Yoan, Popowycz, Florence, Fournet, Guy, Hassan, Moustapha, Echalier, Aude, Bernard, Philippe, Endicott, Jane, Joseph, Benoît, Meijer, Laurent
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.09.2008
• Subjects: Animals; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Bridged Bicyclo Compounds, Heterocyclic - pharmacokinetics; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cell Death - drug effects; Cell Line, Tumor; Crystallography, X-Ray; cyclin; Cyclin A - metabolism; cyclin-dependent kinase; Cyclin-Dependent Kinase 2 - metabolism; Female; Humans; kinase inhibitors; Mcl-1; Medicin och hälsovetenskap; Mice; Mice, Inbred BALB C; Models, Biological; Models, Molecular; Neoplasm Proteins - metabolism; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Purines - chemistry; Purines - pharmacology; roscovitine; Swine; Tissue Extracts - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-08-0080

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 Ser 2 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 p21 CIP1 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. [Mol Cancer Ther 2008;7(9):2713–24]