Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine.

摘要: The G1 restriction point is critical for regulating the cell cycle and controlled by Rb pathway (CDK4/6-cyclin D1-Rb-p16/ink4a). This important because of its inactivation in a majority human tumors. Transition through requires phosphorylation retinoblastoma protein (Rb) CDK4/6, which are highly validated cancer drug targets. We present identification characterization potent CDK4/6 inhibitor, LY2835219. LY2835219 inhibits CDK4 CDK6 with low nanomolar potency, resulting arrest inhibition proliferation, activity specific Rb-proficient cells. In vivo target studies show inhibitor phosphorylation, induces complete suppresses expression several Rb-E2F-regulated proteins 24 hours after single dose. Oral administration tumor growth xenografts representing different histologies tumor-bearing mice. effective well tolerated when administered up to 56 days immunodeficient mice without significant loss body weight or outgrowth. calu-6 xenografts, combination gemcitabine enhanced antitumor arrest, but was associated reduction ribonucleotide reductase expression. These results suggest may be used alone standard-of-care cytotoxic therapy. summary, we have identified potent, orally active small-molecule that xenograft currently clinical development.