Palbociclib (PD0332991) Isethionate

IC50: Palbociclib is an orally active, potent and highly selective inhibitor of CDK4 and CDK6, with IC50 values for CDK4/cyclinD1, CDK4/cyclinD3 and CDK6/cyclinD2 of 11, 9 and 15 nmol/l, respectively.

Cyclin-dependent kinases (CDKs) are a family of protein kinases first discovered for their role in regulating the cell cycle. They are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells. A cyclin-dependent kinase inhibitor (CKI) is a protein that interacts with a cyclin-CDK complex to block kinase activity, usually during G1 or in response to signals from the environment or from damaged DNA. Palbociclib is an experimental drug for the treatment of breast cancer being developed by Pfizer. It is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6.

In vitro: Half-maximal inhibitory concentrations (IC50) of PD-0332991 were determined with cell line proliferation assays. Resutls showed that IC50 values for PD-0332991 ranged from 25.0 nM to 700 nM, and the agent demonstrated G0/G1 cell-cycle arrest, induction of late apoptosis, and blockade of RB phosphorylation. Through genotype and expression data p16, p15 and E2F1 were identified as having significant association between loss and sensitivity to PD-0332991: p16 (p=0.021), p15 (p=0.047), and E2F1 (p=0.041) [1].

In vivo: Oral administration of PD 0332991 to mice bearing the Colo-205 human colon carcinoma produces marked tumor regression. Therapeutic doses of PD 0332991 cause elimination of phospho-Rb and the proliferative marker Ki-67 in tumor tissue and down-regulation of genes under the transcriptional control of E2F. The results indicate that inhibition of Cdk4/6 alone is sufficient to cause tumor regression and a net reduction in tumor burden in some tumors [2].

Clinical trial: In a phase 2 trial reported at the April 2014 annual meeting of the American Association for Cancer Research, the addition of palbociclib to letrozole was shown to significantly slow the progression of advanced cancer (median progression-free survival increased from 10.2 months to 20.2 months), but was not shown to have a statistically significant effect on increasing patients' overall survival times. A potentially confirmatory phase 3 trial, PALOMA-2, has fully enrolled patients. The drug received an accelerated approval from the Food and Drug Administration on February 3, 2015, as a treatment (in combination with letrozole) for patients with estrogen receptor-positive advanced breast cancer (http://en.wikipedia.org/wiki/Palbociclib).

References:
[1] Logan JE, Mostofizadeh N, Desai AJ, VON Euw E, Conklin D, Konkankit V, Hamidi H, Eckardt M, Anderson L, Chen HW, Ginther C, Taschereau E, Bui PH, Christensen JG, Belldegrun AS, Slamon DJ, Kabbinavar FF.  PD-0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, demonstrates inhibition of proliferation in renal cell carcinoma at nanomolar concentrations and molecular markers predict for sensitivity. Anticancer Res. 2013;33(8):2997-3004.
[2] Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, Pryer NK, Toogood PL.  Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004;3(11):1427-38.