Palbociclib

Palbociclib, also known as PD 0332991, is an orally active selective inhibitor of CDK4 (cyclin dependent kinase 4) and CDK6. Palbociclib has potent anti-proliferative activity and induces cell cycle arrest in cancer cells. It is used in the treatment of of ER (estrogen receptor) positive/HER2-negative advanced metastic breast cancer in combination with endocrine therapy, CDKs (cyclin-dependent kinases) are a family of 20 kinases known for their role in regulating cell cycle, transcription and splicing. CDKs are organized in a pathway that safeguards the replication of DNA in each cell during cell division. The activity of CDKs is regulated by cyclins. Together, CDK and cyclins drive the cell cycle by phosphorylating other proteins. Several members of the CDK family have unique tissue specific functions and dysregulation of CDKs and their cyclin partners are associated with a range of tumor types. CDKs have emerged as potential therapeutic targets. Cereblon (CRBN) is the substrate-binding component of the E3 protein ligase complex DDB1(damage specific DNA binding protein 1)-CUL4A (cullin-4)-RBX1 (ring-box 1), which is involved in the ubiquitination and proteasomal degradation of target proteins. Binding of CRBN to a substrate engages its E3 ligase activity and results in the ubiquitination and ultimate degradation of the substrate. Many proteins are known targets of CRBN, including several transcription factors, growth factors and kinases. CRBN has become a target of choice for the development of many PROTACs (proteolysis targeting chimera) with therapeutical interest. Palbociclib, an CDK4/6 inhibitor, used in the treatment of of ER (estrogen receptor) positive/HER2-negative advanced metastic breast cancer in combination with endocrine therapy, is an example of the therapeutic importance of moecules targeting CDKs.