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Clinical CDK4/6 inhibitors induce selective and immediate dissociation of p21 from cyclin D-CDK4 to inhibit CDK2 - PubMed

Clinical CDK4/6 inhibitors induce selective and immediate dissociation of p21 from cyclin D-CDK4 to inhibit CDK2 - PubMed

Source : https://pubmed.ncbi.nlm.nih.gov/34099663/

Since their discovery as drivers of proliferation, cyclin-dependent kinases (CDKs) have been considered therapeutic targets. Small molecule inhibitors of CDK4/6 are used and tested in clinical trials to treat multiple cancer types. Despite their clinical importance, little is known about how CDK4/6 ...

  • June 23, 2021

    Key Points
    • In the current mechanistic study, investigators developed a method to measure the stability of protein complexes in live cells. Their goal was to ascertain how the function of dimeric and trimeric CDK complexes are mediated with the nucleus by CDK4/6 inhibitors.
    • “We show CDK4/6 inhibitors rapidly access already formed cyclin D-CDK4-p21 trimeric complexes to lower p21 affinity without preventing the formation of dimeric and trimeric complexes,” the authors wrote. “Unexpectedly, treatment with clinical CDK4/6 inhibitors results in an immediate accelerated dissociation of p21 only from cyclin D-CDK4-p21 complexes but not from cyclin D-CDK6-p21 complexes or complexes containing p27. Moreover, we find that the dissociation of p21 from cyclin D-CDK4-p21 complexes induced by clinical CDK4/6 inhibitors results in rapid inhibition of CDK2 kinase activity by binding of the released p21.”
    • In the aggregate, the investigators demonstrated that clinical CDK4/6 inhibitors to block cell-cycle entry in two ways. First, they function in a CDK4-restricted non-catalytic role to indirectly inactivate CDK2 complexes by means of p21 redistribution. Second, they act in a catalytic role to directly inactivate CDK4 and CDK6 kinase activity.