Third generation CDK inhibitors selectively inhibit CDK4/6 with potent efficacy and reduced toxicity, such as the FDA approved palbociclib ( 1), ribociclib ( 2), and abemaciclib ( 3) ( Figure 2). However, in recent years, the interest in identifying inhibitors of specific kinases with targeted action on tumor cells and with less toxic effects, has led to the discovery of selective CDK4/6 inhibitors. The toxicity of these compounds is associated with the multi-target activity against isoforms fundamental for the proliferation (CDK1) and survival (CDK9) of normal cells.

Second generation inhibitors (dinaciclib) were developed with the aim to increase selectivity and potency, but demonstrated limited efficacy and considerable toxicity in clinical studies. First generation inhibitors (flavopiridol and roscovitine) demonstrated an inadequate balance between efficacy and toxicity, due to their action on several kinases (pan-inhibitors). Over the years several CDK inhibitors have been developed and tested in different types of cancer.

Figure 17 ep 1