Authors

Discussion

The serum and glucocorticoid kinases (SGKs), a subfamily of the AGC kinases, are comprised of three highly homologous isoforms. SGKs have been increasingly implicated in oncogenic signaling, most notably in estrogen receptor positive (ER+) breast cancer; SGK1 and SGK3 become essential in models of ER+ breast cancer where AKT or PI3K is inhibited.

Our work involved structure-based optimisation of a low micromolar pyrazole amide HTS hit and led to the identification of a sub-set of basic analogues with 50-fold improved potency against SGK3 and attractive PK properties. A leading compound resulted in significant reduction of the SGK3-relevant biomarker pNDRG1 following oral dosing in a mouse tumour xenograft model. Selectivity issues with the AGC-family kinase ROCK1 and susceptibility to metabolism by aldehyde oxidase were addressed by appropriate modifications to the hinge-binding heterocycle and pendent aromatic ring.