摘要：

4410 The cyclin-dependent kinases (CDKs) are essential for regulation of the cell cycle in proliferating cells. A number of inhibitors of CDKs have been proposed as effective anti-cancer therapeutics; several have entered the clinic, the most recent being selective CDK2 and CDK4 inhibitors. We have identified the 2, 4-diamino-5-oxo-pyrimidine as a potent and selective ATP competitive inhibitor of cycB-CDK1, cycE-CDK2 and cycD1-CDK4. In cell-free assays, the CDK inhibitor (CDKi) strongly inhibits all three kinases (Ki = 1-3 nM). It is highly selective for CDK1, 2, and 4 and is not active (Ki >5,000 nM) against a panel of 19 other kinases. The compound has demonstrated significant inhibitory activity against a variety of tumor types both in vitro and in vivo . In vitro , CDKi effectively inhibits the proliferation of tumor cell lines independent of histological type and MDR or p53 status, with IC50 values ranging from 0.05-0.60 μM. The growth inhibitory activity of the compound is manifested by a cell cycle block at G1 and G2 and a demonstrated ability to induce apoptosis. CDKi has also been shown to reduce phosphorylation of the retinoblastoma protein (pRb) in cells at specific cyc-CDK phosphorylation sites. In vivo , CDKi has shown anti-tumor activity in all of the models tested to date. CDKi was efficacious when dosed orally at or below the MTD in 6 of 6 established tumor models in rodents with continuous daily dosing as well as with intermittent once weekly dosing. CDKi was equally active when dosed once a week intravenously in 5 of 5 established tumor models. At the efficacious exposures in the MTLn3 rat mammary adenocarcinoma model, CDKi inhibited phosphorylation of pRb in tumors and in rat peripheral blood mononuclear cells (PBMCs). Inhibition of pRb phosphorylation in human PBMCs treated ex-vivo with CDKi has also been demonstrated, thus indicating a potential pharmacodynamic biomarker for clinical use. The selective kinase inhibition profile and the preclinical anti-tumor activity of CDKi suggest that it could be a new candidate for the treatment of solid tumors.

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