Cdc25B phosphatase inhibitors in cancer therapy: latest developments, trends and medicinal chemistry perspective.
The Cdc25 phosphatases (Cdc25A, Cdc25B, and Cdc25C in humans), which are responsible for dephosphorylating specific tyrosine/threonine residues on cyclin dependent kinases (CDKs), function as essential regulators of cell cycle control during normal eukaryotic cell division and as mediators of the checkpoint response in cells with DNA damage. Because overexpression of Cdc25A and Cdc25B has been linked to numerous cancers and often correlates with a poor clinical outcome, both academia and industry have devoted substantial research effort in establishing the basic underlying molecular mechanisms and in identifying novel, specific and potentially useful inhibitors of Cdc25 as potential anticancer drugs. Over the past year, dozens of research papers and patent applications describing new Cdc25 inhibitors belonging to different structural classes have been disclosed. In this review, we give an overview on the current status in the field of medicinal chemistry of Cdc25B inhibitors. In addition, molecular modeling studies aimed to clarify the molecular mechanism of inhibition as well as the pharmacophoric features critical for design of new and selective Cdc25B inhibitors are also discussed.
Lavecchia
Antonio
A
Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli "Federico II", Facoltà di Farmacia, D. Montesano 49, I-80131 Napoli, Italy. lavecchi@unina.it
Coluccia
Antonio
A
Di Giovanni
Carmen
C
Novellino
Ettore
E
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D020687:cdc25 Phosphatases