3DOG

Structure of Thr 160 phosphorylated CDK2/cyclin A in complex with the inhibitor N-&-N1

Summary for 3DOG

• Entry DOI: 10.2210/pdb3dog/pdb
• Descriptor: Cell division protein kinase 2, Cyclin-A2, (2R)-2-{[4-(benzylamino)-8-(1-methylethyl)pyrazolo[1,5-a][1,3,5]triazin-2-yl]amino}butan-1-ol, ... (5 entities in total)
• Functional Keywords: ser/thr protein kinase; transferase; phosphorylation; cell cycle, atp-binding, cell cycle, cell division, kinase, mitosis, nucleotide-binding, phosphoprotein, polymorphism, serine/threonine-protein kinase, transferase, cyclin, cytoplasm, nucleus
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: P30274
• Total number of polymer chains: 4
• Total formula weight: 129892.25

Authors

Echalier, A.,Endicott, J. (deposition date: 2008-07-04, release date: 2008-09-30, Last modification date: 2024-11-06)

Primary citation

Bettayeb, K.,Sallam, H.,Ferandin, Y.,Popowycz, F.,Fournet, G.,Hassan, M.,Echalier, A.,Bernard, P.,Endicott, J.,Joseph, B.,Meijer, L.
N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine.
Mol.Cancer Ther., 7:2713-2724, 2008

PubMed 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.

PubMed: 18790752
DOI: 10.1158/1535-7163.MCT-08-0080

Experimental method

X-RAY DIFFRACTION (2.7 Å)