PD 0332991 HCl

PD 0332991 is an orally active, selective inhibitor of the cyclin D kinases Cdk4 (IC₅₀ = 11 nM) and Cdk6 (IC₅₀= 16 nM) with no activity against a panel of 36 additional protein kinases. It has been reported to have antiproliferative activity against retinoblastoma-positive tumor cells, blocking retinoblastoma phosphorylation and inducing G₁ arrest at nanomolar concentrations. PD 0332991 can inhibit the growth of certain ER-positive or HER2-amplified breast cancer cells (IC₅₀s as low as 4 nM) and demonstrates synergy with tamoxifen and trastuzumab, respectively. PD 0332991 inhibition of Cdk4 activity has been used to demonstrate a role for insulin-activated cyclinD1-Cdk4 signaling in the control of glucose metabolism that is independent of cell cycle progression.

PD 0332991 is an orally active, selective CDK4/6 inhibitor that blocks pRb phosphorylation at serine 780 and 795 in the low nanomolar range and is in clinical development for the treatment of solid tumors[3][4].

A cell-permeable, orally available and brain permeant, non-toxic pyridopyrimidinone compound that acts as a potent, selective, reversible, ATP competitive inhibitor of Cdk4 and Cdk6 (IC₅₀ = 11, 9, and 15 nM for Cdk4/D1, Cdk4/D3 and Cdk6/D2, respectively). Hence, it reduces retinoblastoma protein phosphorylation at Ser780/Ser795 (IC₅₀ = 66 nM in MDA-435 cells) and arrests cell cycle at G1 phase. Acts as a cytostatic agent, but does induce apoptotic cell death when used alone. However, it potentiates the cytotoxicity of dexamethasone (>Cat. No. 265005), bortezomib (>Cat. No. 504314), and tamoxifen (Cat. No. 579000) in estrogen receptor (ER)-positive cell lines. Exhibits only a trivial inhibitory activity towards Cdk2/E2, Cdk2/A, Cdk1/B and Cdk5/p25 in a 36-kinase panel (IC₅₀ >10 μM). Improves endoderm differentiation of late G1-human embryonic stem cells expressing Smad2 or Smad3 (~ 750 nM) and further enhances endoderm differentiation into hepatic and pancreatic progenitor cells. Shown to regress the growth of human breast tumor xenografts in murine models (~150 mg/kg, p.o., daily).

Cell permeable: yes

CDK4/cyclin D1

[1] ivan diaz-padilla, lillian l. siu and ignacio duran. cyclin-dependent kinase inhibitors as potential targeted anticancer agents. invest new drugs. 2009, 27: 586–594.
[2] richard s finn, judy dering, dylan conklin, ondrej kalous, david j cohen, amrita j desai, charles ginther, mohammad atefi, isan chen, camilla fowst, gerret los and dennis j slamon. pd 0332991, a selective cyclin d kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. breast cancer research. 2009, 11: r77.
[3]Nguyen, L., Zhong, W.-Z., Painter, C. L., Zhang, C., Rahavendran, S. V., & Shen, Z. (2010). Quantitative analysis of PD 0332991 in xenograft mouse tumor tissue by a 96-well supported liquid extraction format and liquid chromatography/mass spectrometry. Journal of Pharmaceutical and Biomedical Analysis, 53(3), 228–234. https://doi.org/10.1016/j.jpba.2010.02.031
[4]Nemoto, A., Saida, S., Kato, I., Kikuchi, J., Furukawa, Y., Maeda, Y., Akahane, K., Honna-Oshiro, H., Goi, K., Kagami, K., Kimura, S., Sato, Y., Okabe, S., Niwa, A., Watanabe, K., Nakahata, T., Heike, T., Sugita, K., & Inukai, T. (2016). Specific Antileukemic Activity of PD0332991, a CDK4/6 Inhibitor, against Philadelphia Chromosome–Positive Lymphoid Leukemia. Molecular Cancer Therapeutics, 15(1), 94–105. https://doi.org/10.1158/1535-7163.mct-14-1065