Palbociclib

Maintaining cell-cycle control has become a mainstay in treatment for many cancers. Cell-cycle manipulation can be especially valuable in breast cancer tumor cells that will often express hormone receptors that are amenable to anti-hormone receptor-targeted therapies. Despite these treatments, patients often progress, leading to other targeted agents being investigated to help promote progression-free survival. Cyclin-dependent kinases (CDKs) have been identified as contributors in the process of cell division. Combining inhibitors of CDKs with traditional endocrine treatments has shown significant progression-free survival in patients with metastatic breast cancer. One such CDK inhibitor, palbociclib, has shown great promise in the treatment of hormone receptor-positive breast cancer. In this article we review the traditional hormonal treatments of breast cancer, how CDK inhibition is beneficial in the treatment of this disease, and the preclinical and clinical data supporting the use of this medication.

Palbociclib is the first U.S. Food and Drug Administration-approved cyclin-dependent kinase inhibitor indicated in combination with letrozole for the treatment of breast cancer. Development of a selective method for the determination of any impurities contained in this drug is significantly important to ensure the quality and safety of palbociclib. In this study, a reliable reversed-phase HPLC method for the separation and determination of eight potential impurities was developed and validated. The structures of two new compounds and six other process-related impurities were characterized and confirmed by MS, NMR, and IR. Based on spectral analysis and available knowledge of the synthetic route of palbociclib, these two new compounds were designated as 6-acetyl-8-cyclopentyl-5-methyl-2-{[3-(piperazin-1-yl)pyridin-2yl]amino}pyrido [2,3-d]pyrimidin-7(8H)-one and 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(4-t-butyloxycarbonyl-)-(piperazin-1-yl)pyridin-2yl]amino}pyrido [2,3-d]pyrimidin-7(8H)-one.

Up to 30% of patients with acute myeloid leukemia (AML) have constitutively activating internal tandem duplications (ITDs) of the FLT3 receptor tyrosine kinase. Such mutations are associated with a poor prognosis and a high propensity to relapse after remission. FLT3 inhibitors are being developed as targeted therapy forFLT3-ITD+AML; however, their use is complicated by rapid development of resistance, illustrating the need for additional therapeutic targets. We show that the FDA-approved CDK4/6 kinase inhibitor palbociclib induces apoptosis of FLT3-ITD leukemic cells. The effect is specific forFLT3-mutant cells and is ascribed to the transcriptional activity of CDK6: CDK6 but not its functional homolog CDK4 is found at the promoters of theFLT3andPIM1genes, another important leukemogenic driver. There CDK6 regulates transcription in a kinase-dependent manner. Of potential clinical relevance combined treatment with palbociclib and FLT3 inhibitors results in synergistic cytotoxicity.

Importance: More than 90% of well-differentiated or dedifferentiated liposarcomas (WD/DDLS) have CDK4 amplification. The selective CDK4 and CDK6 inhibitor palbociclib inhibits growth and induces senescence in liposarcoma cell lines and xenografts. Our prior phase 2 study demonstrated that treatment with palbociclib (200 mg daily for 14 days every 21 days) resulted in clinical benefit in WD/DDLS but moderate hematologic toxic effects. It is important to understand whether palbociclib at a new dose and schedule-125 mg daily for 21 days every 28 days-results in clinical benefit and manageable toxic effects.