Cyclin-dependent kinases (CDKs) are serine/threonine kinases whose activity depends on a regulatory subunit-a cyclin. CDKs are relatively small proteins, with molecular weights ranging from 34 to 40 kDa. What’s more, CDKs play important roles in the control of cell division and modulate transcription in response to several extra- and intracellular cues. By definition, a CDK binds a regulatory protein called a cyclin. Thus, without cyclin, CDK has little kinase activity; only the cyclin-CDK complex is an active kinase.
CDK4 and CDK6 and their activating partners, D-type cyclins, link the extracellular environment with the core cell-cycle machinery. Thus, in normal cells, the activity of cyclin D-CDK4/6 is controlled by the extracellular pro-proliferative or inhibitory signals. In contrast, in many cancers, cyclin D-CDK4/6 kinases are hyperactivated and become independent of mitogenic stimulation, thereby driving uncontrolled tumor cell proliferation. Therefore, small-molecule inhibitors of CDK4/6 have exhibited great effects in the research of hormone receptor-positive breast cancers. Unexpectedly, recent work indicates that inhibition of CDK4/6 affects a wide range of cellular functions, such as tumor cell metabolism.
Palbociclib (PD 0332991) is a potent, selective and orally active CDK4 and CDK6 inhibitor.
In the G1 phase of the cell cycle, mammalian cells must pass a checkpoint, known as the restriction point “R”, in order to complete the cell cycle and divide. Palbociclib can prevent the cell from passing R and exiting G1, and in turn from proceeding through the cell cycle. Thus, Palbociclib inhibits the growth of cancer cells. Besides, Palbociclib produces rapid tumor regressions and delays tumor growth. Therefore, Palbociclib is effective in the research of hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer.
All in all, Palbociclib is a selective and orally active CDK4 and CDK6 inhibitor with anti-cancer activity.
References:
[1]. Malumbres M. Genome Biol. 2014;15(6):122.
[2]. Fassl A, et, al. Science. 2022 Jan 14;375(6577):eabc1495.
[3]. Singh A, et, al. ACS Chem Biol. 2016 Nov 18;11(11):3214-3225.