Fig. 9.

Proposed mechanism of action of palbociclib and dinaciclib in PAH. Multiple growth factors, cytokines, and mitogens induce the activation of cyclin-dependent kinases (CDKs), e.g., by increasing the expression of cyclin D1. Palbociclib specifically targets active complexes consisting of cyclin D1 and CDK4 or CDK6, whereas dinaciclib blocks the activity of the cyclin E-CDK2 complex. This leads to reduced levels of phosphorylated Rb protein and, as a consequence, transcriptional repression of E2F downstream target genes, e.g., Cyclin A2, CDK1, and PCNA. Thus, palbociclib (and dinaciclib) interfere with cell cycle progression from G1 into S phase, causing a reduction of proliferation of pulmonary vascular cells