SGK1-inh is an inhibitor of SGK1 with an IC50 of 4.8nM in a recombinant SGK1 kinase assay, with activity also towards SGK2 and SGK3 (IC50 of 2.8 nM and 590nM respectively). The selectivity of SGK1-inh was tested in vitro at 1μM (200-fold higher than the SGK1 inhibitory dose) against 140 human kinases and showed remarkable activity against SGK1. Although there was no activity against AKT1, PDK1, PKC or RSK, there was inhibition of SK6 due to similarity of their catalytic sites. Further analyses demonstrated that SGK1-inh does not have activity towards SK6 at concentrations below 20-30μM. SGK1-inh was also shown not to inhibit mTORC1. Computational studies suggest that SGK1 acts as a type-II kinase ATP-competitive inhibitor binding preferentially to the inactive conformation of the kinase. In vitro treatment of HOC1954 and JIMT1 cells with BYL719 and SGK1-inh abrogated pNDRG1 (T346) as well as mTORC1 signalling. There was greater inhibition of cell viability of BYL719-resistant cell lines treated with a combination of BYL719 and SGK1-inh. Furthermore, the combination of BYL719 and SGK1-inh reduced tumor burden in xenograft models. This compound is an important tool in understanding the mechanisms of protein-kinase regulation and determining critical points of pharmacological intervention for improved therapeutic options in oncogene-driven cancers such as breast cancer.
Systematic Name: N-(4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl)-2,3-dichlorobenzenesulfonamide
Mol Wt: 435.28
Halland N, et al. Discovery of N-[4-(1H-Pyrazolo[3,4-b]pyrazin-6-y)phenyl]-sulfonamidesas highly active and selective SGK1 inhibitors. ACS Med.Chem. Lett. (2015). 6:73-78.
Castel P et al. PDK1-SGK1 signalling sustains AKT-independent mTORC1 activation and confers resistance to PI3K α inhibition. Cancer Cell (2016). 2016.06.004 [Epub ahead of print].
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