Abstract B233: Identification and characterization of LY2835219: A potent oral inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6) with broad in vivo antitumor activity.

Dysregulation of the cell cycle, which normally regulates cell proliferation in response to mitogenic signaling and other extracellular stimuli, is a hallmark of cancer. The G1 restriction point is a primary mechanism controlling cell cycle progression and is controlled by the CDK4/6 pathway (CDK4/6-cyclin D1-Rb-CDKN2). The importance of this pathway is highlighted by inactivation of restriction point control in a majority of human tumors. Transition through the restriction point requires phosphorylation of Rb by CDK4/6, and these kinases are considered highly validated cancer drug targets. We have identified and characterized a potent and selective dual CDK4/6 inhibitor, LY2835219. Preclinical characterization was performed with the monomesylate salt (LY2835219-MsOH), which inhibits these kinases with a IC50 of 2 and 10 nM for CDK4 and CDK6, respectively. In vitro, LY2835219-MsOH is a potent inhibitor of Rb phosphorylation resulting in a G1 arrest, and its activity is specific for tumors that have functional Rb protein. In a multiplexed in vivo target inhibition assay (IVTI), LY2835219-MsOH is a potent inhibitor of Rb phosphorylation and induces complete cell cycle arrest 24 hrs after a single dose. In tumor-bearing mice, oral administration of LY2835219-MsOH inhibits tumor growth in a dose-dependent manner in colon (colo-205), glioblastoma (U87MG), acute myeloid leukemia (MV4–11), mantle cell lymphoma (Jeko-1), and lung (H460) xenografts. LY2835219-MsOH may be administered up to 56 days without adverse events or tumor outgrowth. LY2835219-MsOH enhances the in vivo activity of cytotoxic drugs, suggesting that this novel CDK4/6 inhibitor can be used in combination with these anti-neoplastic agents. In summary, we have identified an oral small molecule inhibitor of CDK4/6 that may provide therapeutic benefit to cancer patients with tumors that have functional Rb protein. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B233.