Presentation Abstract
Abstract Number: 749
Presentation Title: Highly potent and orally available SIK2 inhibitors block growth of human ovarian cancer cells in culture and xenografts
Presentation Time: Sunday, Apr 06, 2014, 1:00 PM - 5:00 PM
Location: Hall A-E, Poster Section 31
Poster Board Number: 22
Author Block: Albandri Alfredi1, Shu Zhang1, Weiqu Mao1, Yan Wang1, Hiroshi Takemori2, Zhen Lu1, Robert C. Bast, Jr.1, Hariprasad Vankayalapati1. 1University of Texas M.D. Anderson Cancer Center, Houston, TX; 2National Institute of Biomedical Innovation (NIBIO), Osaka, Japan; 3Arrien Pharmaceuticals, Salt Lake City, UT
Abstract Body: Salt Inducible Kinase 2 (SIK2) is a Ser/Thr kinase required for centrosome splitting and bipolar mitotic spindle formation. SIK2 is overexpressed in 30% of ovarian cancers associated with a poor prognosis. Knockdown of SIK2 with siRNA has inhibited ovarian cancer cell growth and enhanced paclitaxel sensitivity in cell culture and in xenografts. Given the challenges of delivering siRNA to cancer cells in vivo, we have sought small molecule inhibitors of SIK2 to permit clinical trials, alone and in combination with paclitaxel. Fragment-based design strategies utilizing SIK2 ATP-binding site residues, scaffold-hopping, SIK2 binding assay and subsequent SAR have led to the discovery of potent, selective, orally bioavailable first-in-class SIK2 inhibitors. Here we describe the identification and the preclinical characterization of ARN-3236 and its novel analogue ARN-3252 belonging to the same chemical class, suitable for oral administration. ARN-3236 and ARN-3252 compounds are highly potent (IC50: 1 and 5 nM), ATP competitive SIK2 inhibitors, characterized by high selectivity when tested against a panel of more than 456 kinases. ARN-3236 and ARN-3252 potently blocked proliferation of human ovarian cancer cell lines with endogenous SIK2 activation including OVCAR-3, SKOv3, HEY and ES-2 with an IC50 between 0.5 to 3.0 uM. Inhibition of proliferation has been observed in 9 additional ovarian cancer cell lines. The ARN-3236 and ARN-3252 exhibit a promising in vitro ADME profile and favorable in vivo PK parameters in mice and rats, including oral bioavailability. When tested in vivo in three murine subcutaneous xenograft models employing OVCAR-3, SKOv3 and ES-2 cells, ARN-3236 displayed dose-dependent tumor growth inhibition following daily oral administration at 30, 60 and 100 mg/Kg, with tumor regression observed at these dose levels. The lead identification, optimization, SAR, PK, single agent efficacy, efficacy in combination with paclitaxel and dose-dependent target modulation and the maintenance of SIK2 phosphorylation inhibition data will be presented. Given these specific small molecule inhibitors, SIK2 may provide a valuable target for treatment of a subset of human ovarian cancers.