Abstract LB-16: Discovery of novel SGK1 inhibitors by a fragment-based approach: Generating patentable, chemically tractable and ligand efficient leads

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Triple negative (ER, PR and HER2/neu negative) breast cancer (TNBC) can have an unfavorable prognosis compared to other breast cancers. TNBC is more difficult to treat since most targeted breast cancer therapies are directed at one of the three receptors. Aggressive combinatorial therapies are usually required and the cytotoxic agents used in these regimens frequently loose effectiveness with time. Serum and glucocorticoid-regulated kinase 1 (SGK1) (a serine/threonine protein kinase), promotes the growth and invasiveness of breast cancer cells. SGK1 is a key protein regulated by the glucocorticoid receptor (GR). In TNBC tumors, high expression/activity in the GR/SGK axis correlates with shorter survival times and resistance to chemotherapy. The small numbers of SGK1 inhibitors reported in the literature have resulted from screening against other kinases (such as CHK1/azaindoles) and thus are not selective and lack patentable chemical diversity. We describe the identification of novel SGK1 inhibitors using a fragment-based library screening approach. The BioBlocks Leap-To-Lead platform contains a library of novel fragment-like compounds that span a range of polarities and sizes without compromising on flexibility. For example, this 275 compound library has an average molecule weight of 160 Da; AlogP, 1.1; hydrogen bond donors, 1.1; hydrogen bond acceptors, 2.2, and rotatable bonds, 0.7 yet still contains 114 unique rings. The library was screened against fully activated human SGK1 in an ADP-Glo assay using physiologically relevant peptide substrate and an optimal ATP concentration to also identify non-classical kinase inhibitor mode binders. The fragment library was screened at 2 mM and hits were profiled in IC50 dose response. From these, several novel chemical matter hit compounds were selected that had ligand efficiency values greater than 0.3 and spanned IC50 values from 75 µM to 2000 µM. In summary, a fragment-based screening approach was used to identify several novel scaffolds that represent both classical and non-classical kinase inhibitor binding modes as hit-to-lead starting points for the optimization of novel, potent and selective SGK1 inhibitors. Citation Format: Gordon Alton, Warren Wade, Laura Lingardo, Ayse Batova, Tom Smart, Chris Buhr, James W. Zapf, Peter Pallai. Discovery of novel SGK1 inhibitors by a fragment-based approach: Generating patentable, chemically tractable and ligand efficient leads. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-16. doi:10.1158/1538-7445.AM2014-LB-16