Recent advances in cyclin-dependent kinase inhibition. Purine-based derivatives as anti-cancer agents. Roles and perspectives for the future.
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 structure-based 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.
Haesslein
Jean-Luc
JL
Medicinal Chemistry, Drug Innovation and Approval, Aventis Pharma, Paris Research Center, 102 Route de Noisy, Romainville, France, 93235, France. jeanluc.haesslein@aventis.com
Jullian
Nathalie
N
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002986:Clinical Trials as Topic; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000145:classification / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011687:Purines; D000255:Adenosine Triphosphate; D018844:Cyclin-Dependent Kinases