Suining Lee

Aurora Kinase Inhibitors Based on the Imidazo[1,2-a]pyrazine Core: Fluorine and Deuterium Incorporation Improve Oral Absorption and Exposure

Aurora kinases are cell cycle regulated serine/threonine kinases that have been linked to cancer. Compound 1 was identified as a potent Aurora inhibitor but lacked oral bioavailability. Optimization of 1 led to the discovery of a series of fluoroamine and deuterated analogues, exemplified by compound 25, with an improved pharmacokinetic profile. We found that blocking oxidative metabolism at the benzylic position and decreasing the basicity of the amine are important to obtaining compounds with good biological profiles and oral bioavailability.

Discovery of a Potent, Injectable Inhibitor of Aurora Kinases Based on the Imidazo-[1,2-a]-Pyrazine Core

The imidazo-[1,2-a]-pyrazine (1) is a dual inhibitor of Aurora kinases A and B with modest cell potency (IC50 = 250 nM) and low solubility (5 μM). Lead optimization guided by the binding mode led to the acyclic amino alcohol 12k (SCH 1473759), which is a picomolar inhibitor of Aurora kinases (TdF K d Aur A = 0.02 nM and Aur B = 0.03 nM) with improved cell potency (phos-HH3 inhibition IC50 = 25 nM) and intrinsic aqueous solubility (11.4 mM). It also demonstrated efficacy and target engagement in human tumor xenograft mouse models.

Discovery of orally bioavailable imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors.

We report a series of potent imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Optimization of the solvent accessible 8-position led to improvements in both oral bioavailability and off-target kinase inhibition. Compound 25 demonstrates anti-tumor activity in an A2780 ovarian tumor xenograft model.

SCH 2047069, a Novel Oral Kinesin Spindle Protein Inhibitor, Shows Single-Agent Antitumor Activity and Enhances the Efficacy of Chemotherapeutics

Kinesin spindle protein (KSP) is a mitotic kinesin required for the formation of the bipolar mitotic spindle, and inhibition of this motor protein results in mitotic arrest and cell death. KSP inhibitors show preclinical antitumor activity and are currently undergoing testing in clinical trials. These agents have been dosed intravenously using various dosing schedules. We sought to identify a KSP inhibitor that could be delivered orally and thus provide convenience of dosing as well as the ability to achieve more continuous exposure via the use of dose-dense administration. We discovered SCH 2047069, a potent KSP inhibitor with oral bioavailability across species and the ability to cross the blood-brain barrier. The compound induces mitotic arrest characterized by a monaster spindle and is associated with an increase in histone H3 and mitotic protein monoclonal 2 phosphorylation both in vitro and in vivo. SCH 2047069 showed antitumor activity in a variety of preclinical models as a single agent and in combination with paclitaxel, gemcitabine, or vincristine. Mol Cancer Ther; 9(11); 2993–3002. ©2010 AACR.

Abstract 1648: SCH 1473759, a novel aurora inhibitor, demonstrates enhanced antitumor activity in combination with taxanes and KSP inhibitors

Aurora kinases are required for orderly progression of cells through mitosis. Inhibition of these kinases by siRNA or a small molecule inhibitors results in aberrant endoreduplication and cell death. SCH 1473759 is a novel Aurora inhibitor with potent mechanism based cell activity. The compound is active against a large panel of tumor cell lines from different tissue origin and genetic backgrounds. We found that asynchronous cells require 24 hour exposure to SCH 1473759 to induce maximal endoreduplication and cell kill. However, following a taxane or KSP inhibitor mitotic arrest, less than 4-hour exposure was sufficient to induce endoreduplication. This finding correlated with the ability of SCH 1473759 to accelerate exit from mitosis in response to taxane and KSP induced arrest, but not that of a nocodazole arrest. SCH 1473759 demonstrated single agent biomarker and anti-tumor activity in A2780 ovarian xenograft models. Further, efficacy was enhanced in combination with taxotere and found to be most efficacious when SCH 1473759 was dosed 12-hours post taxotere. These findings could have clinical implications for the development of Aurora inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1648.