Jean-luc Haesslein and Nathalie Jullian Pages 1037 - 1050 ( 14 )
Protein kinases (Ser / Thr and Tyr) play a key role in signal transduction pathways. It has been shown that deregulation of the Cdk activity is linked to cell proliferation and cancer. Inhibition of cyclin-dependent kinases (Cdks) is an important target for potential new anti-cancer drugs. Following the discovery of Olomoucine, a wide range of tri-substituted purine derivatives have been synthesized, leading to potent Cdk inhibitors. These purine-derived compounds bind to the ATP pocket of the protein. Of interest for structurebased drug design, the different crystal structures published to date show evidence for three different binding modes for the purine ring, allowing diverse exploration of the ATP binding site. Some examples of synthesis and structure activity relationships are discussed for a set of purine derivatives, tri-substituted on C-2, N-9 and C-6. Finally, in vivo activities are reviewed, as well as the applications in other therapeutic areas.
kinase inhibitors, atp competitive inhibitor, kinase-mediated diseases, treatment of cancer, potent src kinase inhibitors, tricyclic kinase inhibitors
Medicinal Chemistry, Drug Innovation and Approval, Aventis Pharma, Paris Research Center, 102Route de Noisy, 93235 Romainville, France