Fig. 2

Inhibition of G1/S cyclin-dependent kinases by CDK4/6 inhibitors. A The traditional model suggests that CDK4/6 inhibitors inhibit active CDK4/6-cyclin D-p21/p27 holoenzymes, preventing RB phosphorylation by CDK4/6. B Two models suggest mechanisms by which CDK4/6 inhibitors indirectly inhibit CDK2 activity. (I) Guiley et al. propose that CDK4/6 inhibitors bind to monomeric CDK4/6, preventing the formation of CDK4/6-cyclin D-p21/p27 trimers. The free p21 then binds to and inhibits cyclin E/CDK2, preventing RB phosphorylation. This model suggests that the CDK4/6i induces cell cycle arrest through an indirect inhibition of CDK2, rather than inhibition of CDK4/6 activity. (II) Pack et al. propose that CDK4/6i inhibitors do inhibit CDK4/6 catalytic activity directly, but also displace p21 from established CDK4-cyclin D-p21 trimers, again leading to indirect inhibition of cyclin E/CDK2