Cyclin-dependent kinase inhibitors as marketed anticancer drugs: where are we now? A short survey

Abstract

In the early 2000s, the anticancer drug imatinib (Glivec®) appeared on the market, exhibiting a new mode of action by selective kinase inhibition. Consequently, kinases became a validated therapeutic target, paving the way for further developments. Although these kinases have been thoroughly studied, none of the compounds commercialized since then target cyclin-dependent kinases (CDKs). Following a recent and detailed review on the subject by Galons et al., we concentrate our attention on an updated list of compounds under clinical evaluation (phase I/II/III) and discuss their mode of action as ATP-competitive inhibitors. CDK inhibition profiles and clinical development stages are reported for the 14 compounds under clinical evaluation. Also, tentative progress for forthcoming potential ATP non-competitive inhibitors and allosteric inhibitors are briefly described, along with their limitations.

Figure 1

Imatinib (Glivec^®), the first kinase inhibitor.

Figure 2

Cyclin-dependent kinase inhibitors (14 compounds) under clinical evaluation.

Figure 3

Comparison of Astex/Novartis’ LEE-011 and Pfizer’s PD0332991 structures.

Figure 4

3-Aminothioacridinone (3-ATA).

Figure 5

CDK2 allosteric site [74] (reproduction/modification by courtesy of E. Schönbrunn).