Palbociclib

Palbociclib is a highly specific inhibitor of Cdk4 (IC₅₀=11 nM) and Cdk6 (IC₅₀=16 nM), having no activity against a panel of 36 additional protein kinases. IC50 & Target: IC50: 11 nM (Cdk4), 16 nM (Cdk6)^[1] In Vitro: The IC₅₀ of Palbociclib (PD 0332991) for reduction of retinoblastoma (Rb) phosphorylation at Ser⁷⁸⁰ in MDA-MB-435 breast carcinoma cells is 66 nM. Palbociclib is equally effective at reducing Rb phosphorylation at Ser⁷⁹⁵ in this tumor with an IC₅₀ of 63 nM, and similar effects on both Ser⁷⁸⁰ and Ser⁷⁹⁵ phosphorylation are obtained in the Colo-205 colon carcinoma^[1]. The MP-MRT-AN (AN), KP-MRT-RY (RY), G401, and KP-MRT-NS (NS) cell lines are effectively inhibited by Palbociclib (PD) in a concentration-dependent manner in a WST-8 assay. The IC₅₀s are 0.01 µM, 0.01 µM, 0.06 µM, and 0.6 µM, respectively. In contrast, the KP-MRT-YM (YM) cell line is resistant to Palbociclib (IC₅₀>10 µM). The flow cytometry results show that Palbociclib at concentrations between 0 to 1.0 µM induces G1 arrest in the AN, RY, G401 and NS cell lines in a concentration-dependent manner, but has no effect on YM cells. The BrdU incorporation results are consistent with the WST-8 and flow cytometry results: PD reduces BrdU incorporation (indicating G1 arrest) in the AN, RY, G401 and NS cell lines, but not in the YM cell line. Palbociclib, even at a concentration of 0.05 µM, significantly reduces BrdU incorporation in the AN, RY, and G401 cell lines (p<0.05)^[2]. In Vivo: Palbociclib (PD 0332991) exhibits significant antitumor efficacy against multiple human tumor xenograft models. In mice bearing Colo-205 colon carcinoma xenografts (p16 deleted), daily p.o. dosing for 14 days with Palbociclib (150 or 75 mg/kg) produces rapid tumor regressions and a corresponding tumor growth delay of ~50 days with >1 log of tumor cell kill at the highest dose tested. At 37.5 mg/kg, the tumor slowly regressed during treatment. Even at doses as low as 12.5 mg/kg, a 13-day growth delay is obtained indicating a 90% inhibition of tumor growth rate. Likewise, robust antitumor activity is seen in the MDA-MB-435 breast carcinoma (p16 deleted) where complete tumor stasis is apparent at 150 mg/kg and some cell kill is evident at the highest dose^[1].