Development of CDK4/6 Inhibitors: A Five Years Update

The inhibition of cyclin dependent kinases 4 and 6 plays a role in aromatase inhibitor
resistant metastatic breast cancer. Three dual CDK4/6 inhibitors have been approved for the breast
cancer treatment that, in combination with the endocrine therapy, dramatically improved the survival
outcomes both in first and later line settings. The developments of the last five years in the search
for new selective CDK4/6 inhibitors with increased selectivity, treatment efficacy, and reduced
adverse effects are reviewed, considering the small-molecule inhibitors and proteolysis-targeting
chimeras (PROTACs) approaches, mainly pointing at structure-activity relationships, selectivity
against different kinases and antiproliferative activity.